science article about a stem cell research project

• Open access
• Published: 26 February 2019

Stem cells: past, present, and future

• Wojciech Zakrzewski 1 ,
• Maciej Dobrzyński 2 ,
• Maria Szymonowicz 1 &
• Zbigniew Rybak 1  

Stem Cell Research & Therapy volume  10 , Article number:  68 ( 2019 ) Cite this article

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In recent years, stem cell therapy has become a very promising and advanced scientific research topic. The development of treatment methods has evoked great expectations. This paper is a review focused on the discovery of different stem cells and the potential therapies based on these cells. The genesis of stem cells is followed by laboratory steps of controlled stem cell culturing and derivation. Quality control and teratoma formation assays are important procedures in assessing the properties of the stem cells tested. Derivation methods and the utilization of culturing media are crucial to set proper environmental conditions for controlled differentiation. Among many types of stem tissue applications, the use of graphene scaffolds and the potential of extracellular vesicle-based therapies require attention due to their versatility. The review is summarized by challenges that stem cell therapy must overcome to be accepted worldwide. A wide variety of possibilities makes this cutting edge therapy a turning point in modern medicine, providing hope for untreatable diseases.

Stem cell classification

Stem cells are unspecialized cells of the human body. They are able to differentiate into any cell of an organism and have the ability of self-renewal. Stem cells exist both in embryos and adult cells. There are several steps of specialization. Developmental potency is reduced with each step, which means that a unipotent stem cell is not able to differentiate into as many types of cells as a pluripotent one. This chapter will focus on stem cell classification to make it easier for the reader to comprehend the following chapters.

Totipotent stem cells are able to divide and differentiate into cells of the whole organism. Totipotency has the highest differentiation potential and allows cells to form both embryo and extra-embryonic structures. One example of a totipotent cell is a zygote, which is formed after a sperm fertilizes an egg. These cells can later develop either into any of the three germ layers or form a placenta. After approximately 4 days, the blastocyst’s inner cell mass becomes pluripotent. This structure is the source of pluripotent cells.

Pluripotent stem cells (PSCs) form cells of all germ layers but not extraembryonic structures, such as the placenta. Embryonic stem cells (ESCs) are an example. ESCs are derived from the inner cell mass of preimplantation embryos. Another example is induced pluripotent stem cells (iPSCs) derived from the epiblast layer of implanted embryos. Their pluripotency is a continuum, starting from completely pluripotent cells such as ESCs and iPSCs and ending on representatives with less potency—multi-, oligo- or unipotent cells. One of the methods to assess their activity and spectrum is the teratoma formation assay. iPSCs are artificially generated from somatic cells, and they function similarly to PSCs. Their culturing and utilization are very promising for present and future regenerative medicine.

Multipotent stem cells have a narrower spectrum of differentiation than PSCs, but they can specialize in discrete cells of specific cell lineages. One example is a haematopoietic stem cell, which can develop into several types of blood cells. After differentiation, a haematopoietic stem cell becomes an oligopotent cell. Its differentiation abilities are then restricted to cells of its lineage. However, some multipotent cells are capable of conversion into unrelated cell types, which suggests naming them pluripotent cells.

Oligopotent stem cells can differentiate into several cell types. A myeloid stem cell is an example that can divide into white blood cells but not red blood cells.

Unipotent stem cells are characterized by the narrowest differentiation capabilities and a special property of dividing repeatedly. Their latter feature makes them a promising candidate for therapeutic use in regenerative medicine. These cells are only able to form one cell type, e.g. dermatocytes.

Stem cell biology

A blastocyst is formed after the fusion of sperm and ovum fertilization. Its inner wall is lined with short-lived stem cells, namely, embryonic stem cells. Blastocysts are composed of two distinct cell types: the inner cell mass (ICM), which develops into epiblasts and induces the development of a foetus, and the trophectoderm (TE). Blastocysts are responsible for the regulation of the ICM microenvironment. The TE continues to develop and forms the extraembryonic support structures needed for the successful origin of the embryo, such as the placenta. As the TE begins to form a specialized support structure, the ICM cells remain undifferentiated, fully pluripotent and proliferative [ 1 ]. The pluripotency of stem cells allows them to form any cell of the organism. Human embryonic stem cells (hESCs) are derived from the ICM. During the process of embryogenesis, cells form aggregations called germ layers: endoderm, mesoderm and ectoderm (Fig.  1 ), each eventually giving rise to differentiated cells and tissues of the foetus and, later on, the adult organism [ 2 ]. After hESCs differentiate into one of the germ layers, they become multipotent stem cells, whose potency is limited to only the cells of the germ layer. This process is short in human development. After that, pluripotent stem cells occur all over the organism as undifferentiated cells, and their key abilities are proliferation by the formation of the next generation of stem cells and differentiation into specialized cells under certain physiological conditions.

Oocyte development and formation of stem cells: the blastocoel, which is formed from oocytes, consists of embryonic stem cells that later differentiate into mesodermal, ectodermal, or endodermal cells. Blastocoel develops into the gastrula

Signals that influence the stem cell specialization process can be divided into external, such as physical contact between cells or chemical secretion by surrounding tissue, and internal, which are signals controlled by genes in DNA.

Stem cells also act as internal repair systems of the body. The replenishment and formation of new cells are unlimited as long as an organism is alive. Stem cell activity depends on the organ in which they are in; for example, in bone marrow, their division is constant, although in organs such as the pancreas, division only occurs under special physiological conditions.

Stem cell functional division

Whole-body development.

During division, the presence of different stem cells depends on organism development. Somatic stem cell ESCs can be distinguished. Although the derivation of ESCs without separation from the TE is possible, such a combination has growth limits. Because proliferating actions are limited, co-culture of these is usually avoided.

ESCs are derived from the inner cell mass of the blastocyst, which is a stage of pre-implantation embryo ca. 4 days after fertilization. After that, these cells are placed in a culture dish filled with culture medium. Passage is an inefficient but popular process of sub-culturing cells to other dishes. These cells can be described as pluripotent because they are able to eventually differentiate into every cell type in the organism. Since the beginning of their studies, there have been ethical restrictions connected to the medical use of ESCs in therapies. Most embryonic stem cells are developed from eggs that have been fertilized in an in vitro clinic, not from eggs fertilized in vivo.

Somatic or adult stem cells are undifferentiated and found among differentiated cells in the whole body after development. The function of these cells is to enable the healing, growth, and replacement of cells that are lost each day. These cells have a restricted range of differentiation options. Among many types, there are the following:

Mesenchymal stem cells are present in many tissues. In bone marrow, these cells differentiate mainly into the bone, cartilage, and fat cells. As stem cells, they are an exception because they act pluripotently and can specialize in the cells of any germ layer.

Neural cells give rise to nerve cells and their supporting cells—oligodendrocytes and astrocytes.

Haematopoietic stem cells form all kinds of blood cells: red, white, and platelets.

Skin stem cells form, for example, keratinocytes, which form a protective layer of skin.

The proliferation time of somatic stem cells is longer than that of ESCs. It is possible to reprogram adult stem cells back to their pluripotent state. This can be performed by transferring the adult nucleus into the cytoplasm of an oocyte or by fusion with the pluripotent cell. The same technique was used during cloning of the famous Dolly sheep.

hESCs are involved in whole-body development. They can differentiate into pluripotent, totipotent, multipotent, and unipotent cells (Fig.  2 ) [ 2 ].

Changes in the potency of stem cells in human body development. Potency ranges from pluripotent cells of the blastocyst to unipotent cells of a specific tissue in a human body such as the skin, CNS, or bone marrow. Reversed pluripotency can be achieved by the formation of induced pluripotent stem cells using either octamer-binding transcription factor (Oct4), sex-determining region Y (Sox2), Kruppel-like factor 4 (Klf4), or the Myc gene

Pluripotent cells can be named totipotent if they can additionally form extraembryonic tissues of the embryo. Multipotent cells are restricted in differentiating to each cell type of given tissue. When tissue contains only one lineage of cells, stem cells that form them are called either called oligo- or unipotent.

iPSC quality control and recognition by morphological differences

The comparability of stem cell lines from different individuals is needed for iPSC lines to be used in therapeutics [ 3 ]. Among critical quality procedures, the following can be distinguished:

Short tandem repeat analysis—This is the comparison of specific loci on the DNA of the samples. It is used in measuring an exact number of repeating units. One unit consists of 2 to 13 nucleotides repeating many times on the DNA strand. A polymerase chain reaction is used to check the lengths of short tandem repeats. The genotyping procedure of source tissue, cells, and iPSC seed and master cell banks is recommended.

Identity analysis—The unintentional switching of lines, resulting in other stem cell line contamination, requires rigorous assay for cell line identification.

Residual vector testing—An appearance of reprogramming vectors integrated into the host genome is hazardous, and testing their presence is a mandatory procedure. It is a commonly used procedure for generating high-quality iPSC lines. An acceptable threshold in high-quality research-grade iPSC line collections is ≤ 1 plasmid copies per 100 cells. During the procedure, 2 different regions, common to all plasmids, should be used as specific targets, such as EBNA and CAG sequences [ 3 ]. To accurately represent the test reactions, a standard curve needs to be prepared in a carrier of gDNA from a well-characterized hPSC line. For calculations of plasmid copies per cell, it is crucial to incorporate internal reference gDNA sequences to allow the quantification of, for example, ribonuclease P (RNaseP) or human telomerase reverse transcriptase (hTERT).

Karyotype—A long-term culture of hESCs can accumulate culture-driven mutations [ 4 ]. Because of that, it is crucial to pay additional attention to genomic integrity. Karyotype tests can be performed by resuscitating representative aliquots and culturing them for 48–72 h before harvesting cells for karyotypic analysis. If abnormalities are found within the first 20 karyotypes, the analysis must be repeated on a fresh sample. When this situation is repeated, the line is evaluated as abnormal. Repeated abnormalities must be recorded. Although karyology is a crucial procedure in stem cell quality control, the single nucleotide polymorphism (SNP) array, discussed later, has approximately 50 times higher resolution.

Viral testing—When assessing the quality of stem cells, all tests for harmful human adventitious agents must be performed (e.g. hepatitis C or human immunodeficiency virus). This procedure must be performed in the case of non-xeno-free culture agents.

Bacteriology—Bacterial or fungal sterility tests can be divided into culture- or broth-based tests. All the procedures must be recommended by pharmacopoeia for the jurisdiction in which the work is performed.

Single nucleotide polymorphism arrays—This procedure is a type of DNA microarray that detects population polymorphisms by enabling the detection of subchromosomal changes and the copy-neutral loss of heterozygosity, as well as an indication of cellular transformation. The SNP assay consists of three components. The first is labelling fragmented nucleic acid sequences with fluorescent dyes. The second is an array that contains immobilized allele-specific oligonucleotide (ASO) probes. The last component detects, records, and eventually interprets the signal.

Flow cytometry—This is a technique that utilizes light to count and profile cells in a heterogeneous fluid mixture. It allows researchers to accurately and rapidly collect data from heterogeneous fluid mixtures with live cells. Cells are passed through a narrow channel one by one. During light illumination, sensors detect light emitted or refracted from the cells. The last step is data analysis, compilation and integration into a comprehensive picture of the sample.

Phenotypic pluripotency assays—Recognizing undifferentiated cells is crucial in successful stem cell therapy. Among other characteristics, stem cells appear to have a distinct morphology with a high nucleus to cytoplasm ratio and a prominent nucleolus. Cells appear to be flat with defined borders, in contrast to differentiating colonies, which appear as loosely located cells with rough borders [ 5 ]. It is important that images of ideal and poor quality colonies for each cell line are kept in laboratories, so whenever there is doubt about the quality of culture, it can always be checked according to the representative image. Embryoid body formation or directed differentiation of monolayer cultures to produce cell types representative of all three embryonic germ layers must be performed. It is important to note that colonies cultured under different conditions may have different morphologies [ 6 ].

Histone modification and DNA methylation—Quality control can be achieved by using epigenetic analysis tools such as histone modification or DNA methylation. When stem cells differentiate, the methylation process silences pluripotency genes, which reduces differentiation potential, although other genes may undergo demethylation to become expressed [ 7 ]. It is important to emphasize that stem cell identity, together with its morphological characteristics, is also related to its epigenetic profile [ 8 , 9 ]. According to Brindley [ 10 ], there is a relationship between epigenetic changes, pluripotency, and cell expansion conditions, which emphasizes that unmethylated regions appear to be serum-dependent.

hESC derivation and media

hESCs can be derived using a variety of methods, from classic culturing to laser-assisted methodologies or microsurgery [ 11 ]. hESC differentiation must be specified to avoid teratoma formation (see Fig.  3 ).

Spontaneous differentiation of hESCs causes the formation of a heterogeneous cell population. There is a different result, however, when commitment signals (in forms of soluble factors and culture conditions) are applied and enable the selection of progenitor cells

hESCs spontaneously differentiate into embryonic bodies (EBs) [ 12 ]. EBs can be studied instead of embryos or animals to predict their effects on early human development. There are many different methods for acquiring EBs, such as bioreactor culture [ 13 ], hanging drop culture [ 12 ], or microwell technology [ 14 , 15 ]. These methods allow specific precursors to form in vitro [ 16 ].

The essential part of these culturing procedures is a separation of inner cell mass to culture future hESCs (Fig.  4 ) [ 17 ]. Rosowski et al. [ 18 ] emphasizes that particular attention must be taken in controlling spontaneous differentiation. When the colony reaches the appropriate size, cells must be separated. The occurrence of pluripotent cells lasts for 1–2 days. Because the classical utilization of hESCs caused ethical concerns about gastrulas used during procedures, Chung et al. [ 19 ] found out that it is also possible to obtain hESCs from four cell embryos, leaving a higher probability of embryo survival. Additionally, Zhang et al. [ 20 ] used only in vitro fertilization growth-arrested cells.

Culturing of pluripotent stem cells in vitro. Three days after fertilization, totipotent cells are formed. Blastocysts with ICM are formed on the sixth day after fertilization. Pluripotent stem cells from ICM can then be successfully transmitted on a dish

Cell passaging is used to form smaller clusters of cells on a new culture surface [ 21 ]. There are four important passaging procedures.

Enzymatic dissociation is a cutting action of enzymes on proteins and adhesion domains that bind the colony. It is a gentler method than the manual passage. It is crucial to not leave hESCs alone after passaging. Solitary cells are more sensitive and can easily undergo cell death; collagenase type IV is an example [ 22 , 23 ].

Manual passage , on the other hand, focuses on using cell scratchers. The selection of certain cells is not necessary. This should be done in the early stages of cell line derivation [ 24 ].

Trypsin utilization allows a healthy, automated hESC passage. Good Manufacturing Practice (GMP)-grade recombinant trypsin is widely available in this procedure [ 24 ]. However, there is a risk of decreasing the pluripotency and viability of stem cells [ 25 ]. Trypsin utilization can be halted with an inhibitor of the protein rho-associated protein kinase (ROCK) [ 26 ].

Ethylenediaminetetraacetic acid ( EDTA ) indirectly suppresses cell-to-cell connections by chelating divalent cations. Their suppression promotes cell dissociation [ 27 ].

Stem cells require a mixture of growth factors and nutrients to differentiate and develop. The medium should be changed each day.

Traditional culture methods used for hESCs are mouse embryonic fibroblasts (MEFs) as a feeder layer and bovine serum [ 28 ] as a medium. Martin et al. [ 29 ] demonstrated that hESCs cultured in the presence of animal products express the non-human sialic acid, N -glycolylneuraminic acid (NeuGc). Feeder layers prevent uncontrolled proliferation with factors such as leukaemia inhibitory factor (LIF) [ 30 ].

First feeder layer-free culture can be supplemented with serum replacement, combined with laminin [ 31 ]. This causes stable karyotypes of stem cells and pluripotency lasting for over a year.

Initial culturing media can be serum (e.g. foetal calf serum FCS), artificial replacement such as synthetic serum substitute (SSS), knockout serum replacement (KOSR), or StemPro [ 32 ]. The simplest culture medium contains only eight essential elements: DMEM/F12 medium, selenium, NaHCO 3, l -ascorbic acid, transferrin, insulin, TGFβ1, and FGF2 [ 33 ]. It is not yet fully known whether culture systems developed for hESCs can be allowed without adaptation in iPSC cultures.

Turning point in stem cell therapy

The turning point in stem cell therapy appeared in 2006, when scientists Shinya Yamanaka, together with Kazutoshi Takahashi, discovered that it is possible to reprogram multipotent adult stem cells to the pluripotent state. This process avoided endangering the foetus’ life in the process. Retrovirus-mediated transduction of mouse fibroblasts with four transcription factors (Oct-3/4, Sox2, KLF4, and c-Myc) [ 34 ] that are mainly expressed in embryonic stem cells could induce the fibroblasts to become pluripotent (Fig.  5 ) [ 35 ]. This new form of stem cells was named iPSCs. One year later, the experiment also succeeded with human cells [ 36 ]. After this success, the method opened a new field in stem cell research with a generation of iPSC lines that can be customized and biocompatible with the patient. Recently, studies have focused on reducing carcinogenesis and improving the conduction system.

Retroviral-mediated transduction induces pluripotency in isolated patient somatic cells. Target cells lose their role as somatic cells and, once again, become pluripotent and can differentiate into any cell type of human body

The turning point was influenced by former discoveries that happened in 1962 and 1987.

The former discovery was about scientist John Gurdon successfully cloning frogs by transferring a nucleus from a frog’s somatic cells into an oocyte. This caused a complete reversion of somatic cell development [ 37 ]. The results of his experiment became an immense discovery since it was previously believed that cell differentiation is a one-way street only, but his experiment suggested the opposite and demonstrated that it is even possible for a somatic cell to again acquire pluripotency [ 38 ].

The latter was a discovery made by Davis R.L. that focused on fibroblast DNA subtraction. Three genes were found that originally appeared in myoblasts. The enforced expression of only one of the genes, named myogenic differentiation 1 (Myod1), caused the conversion of fibroblasts into myoblasts, showing that reprogramming cells is possible, and it can even be used to transform cells from one lineage to another [ 39 ].

Although pluripotency can occur naturally only in embryonic stem cells, it is possible to induce terminally differentiated cells to become pluripotent again. The process of direct reprogramming converts differentiated somatic cells into iPSC lines that can form all cell types of an organism. Reprogramming focuses on the expression of oncogenes such as Myc and Klf4 (Kruppel-like factor 4). This process is enhanced by a downregulation of genes promoting genome stability, such as p53. Additionally, cell reprogramming involves histone alteration. All these processes can cause potential mutagenic risk and later lead to an increased number of mutations. Quinlan et al. [ 40 ] checked fully pluripotent mouse iPSCs using whole genome DNA sequencing and structural variation (SV) detection algorithms. Based on those studies, it was confirmed that although there were single mutations in the non-genetic region, there were non-retrotransposon insertions. This led to the conclusion that current reprogramming methods can produce fully pluripotent iPSCs without severe genomic alterations.

During the course of development from pluripotent hESCs to differentiated somatic cells, crucial changes appear in the epigenetic structure of these cells. There is a restriction or permission of the transcription of genes relevant to each cell type. When somatic cells are being reprogrammed using transcription factors, all the epigenetic architecture has to be reconditioned to achieve iPSCs with pluripotency [ 41 ]. However, cells of each tissue undergo specific somatic genomic methylation. This influences transcription, which can further cause alterations in induced pluripotency [ 42 ].

Source of iPSCs

Because pluripotent cells can propagate indefinitely and differentiate into any kind of cell, they can be an unlimited source, either for replacing lost or diseased tissues. iPSCs bypass the need for embryos in stem cell therapy. Because they are made from the patient’s own cells, they are autologous and no longer generate any risk of immune rejection.

At first, fibroblasts were used as a source of iPSCs. Because a biopsy was needed to achieve these types of cells, the technique underwent further research. Researchers investigated whether more accessible cells could be used in the method. Further, other cells were used in the process: peripheral blood cells, keratinocytes, and renal epithelial cells found in urine. An alternative strategy to stem cell transplantation can be stimulating a patient’s endogenous stem cells to divide or differentiate, occurring naturally when skin wounds are healing. In 2008, pancreatic exocrine cells were shown to be reprogrammed to functional, insulin-producing beta cells [ 43 ].

The best stem cell source appears to be the fibroblasts, which is more tempting in the case of logistics since its stimulation can be fast and better controlled [ 44 ].

• Teratoma formation assay

The self-renewal and differentiation capabilities of iPSCs have gained significant interest and attention in regenerative medicine sciences. To study their abilities, a quality-control assay is needed, of which one of the most important is the teratoma formation assay. Teratomas are benign tumours. Teratomas are capable of rapid growth in vivo and are characteristic because of their ability to develop into tissues of all three germ layers simultaneously. Because of the high pluripotency of teratomas, this formation assay is considered an assessment of iPSC’s abilities [ 45 ].

Teratoma formation rate, for instance, was observed to be elevated in human iPSCs compared to that in hESCs [ 46 ]. This difference may be connected to different differentiation methods and cell origins. Most commonly, the teratoma assay involves an injection of examined iPSCs subcutaneously or under the testis or kidney capsule in mice, which are immune-deficient [ 47 ]. After injection, an immature but recognizable tissue can be observed, such as the kidney tubules, bone, cartilage, or neuroepithelium [ 30 ]. The injection site may have an impact on the efficiency of teratoma formation [ 48 ].

There are three groups of markers used in this assay to differentiate the cells of germ layers. For endodermal tissue, there is insulin/C-peptide and alpha-1 antitrypsin [ 49 ]. For the mesoderm, derivatives can be used, e.g. cartilage matrix protein for the bone and alcian blue for the cartilage. As ectodermal markers, class III B botulin or keratin can be used for keratinocytes.

Teratoma formation assays are considered the gold standard for demonstrating the pluripotency of human iPSCs, demonstrating their possibilities under physiological conditions. Due to their actual tissue formation, they could be used for the characterization of many cell lineages [ 50 ].

Directed differentiation

To be useful in therapy, stem cells must be converted into desired cell types as necessary or else the whole regenerative medicine process will be pointless. Differentiation of ESCs is crucial because undifferentiated ESCs can cause teratoma formation in vivo. Understanding and using signalling pathways for differentiation is an important method in successful regenerative medicine. In directed differentiation, it is likely to mimic signals that are received by cells when they undergo successive stages of development [ 51 ]. The extracellular microenvironment plays a significant role in controlling cell behaviour. By manipulating the culture conditions, it is possible to restrict specific differentiation pathways and generate cultures that are enriched in certain precursors in vitro. However, achieving a similar effect in vivo is challenging. It is crucial to develop culture conditions that will allow the promotion of homogenous and enhanced differentiation of ESCs into functional and desired tissues.

Regarding the self-renewal of embryonic stem cells, Hwang et al. [ 52 ] noted that the ideal culture method for hESC-based cell and tissue therapy would be a defined culture free of either the feeder layer or animal components. This is because cell and tissue therapy requires the maintenance of large quantities of undifferentiated hESCs, which does not make feeder cells suitable for such tasks.

Most directed differentiation protocols are formed to mimic the development of an inner cell mass during gastrulation. During this process, pluripotent stem cells differentiate into ectodermal, mesodermal, or endodermal progenitors. Mall molecules or growth factors induce the conversion of stem cells into appropriate progenitor cells, which will later give rise to the desired cell type. There is a variety of signal intensities and molecular families that may affect the establishment of germ layers in vivo, such as fibroblast growth factors (FGFs) [ 53 ]; the Wnt family [ 54 ] or superfamily of transforming growth factors—β(TGFβ); and bone morphogenic proteins (BMP) [ 55 ]. Each candidate factor must be tested on various concentrations and additionally applied to various durations because the precise concentrations and times during which developing cells in embryos are influenced during differentiation are unknown. For instance, molecular antagonists of endogenous BMP and Wnt signalling can be used for ESC formation of ectoderm [ 56 ]. However, transient Wnt and lower concentrations of the TGFβ family trigger mesodermal differentiation [ 57 ]. Regarding endoderm formation, a higher activin A concentration may be required [ 58 , 59 ].

There are numerous protocols about the methods of forming progenitors of cells of each of germ layers, such as cardiomyocytes [ 60 ], hepatocytes [ 61 ], renal cells [ 62 ], lung cells [ 63 , 64 ], motor neurons [ 65 ], intestinal cells [ 66 ], or chondrocytes [ 67 ].

Directed differentiation of either iPSCs or ESCs into, e.g. hepatocytes, could influence and develop the study of the molecular mechanisms in human liver development. In addition, it could also provide the possibility to form exogenous hepatocytes for drug toxicity testing [ 68 ].

Levels of concentration and duration of action with a specific signalling molecule can cause a variety of factors. Unfortunately, for now, a high cost of recombinant factors is likely to limit their use on a larger scale in medicine. The more promising technique focuses on the use of small molecules. These can be used for either activating or deactivating specific signalling pathways. They enhance reprogramming efficiency by creating cells that are compatible with the desired type of tissue. It is a cheaper and non-immunogenic method.

One of the successful examples of small-molecule cell therapies is antagonists and agonists of the Hedgehog pathway. They show to be very useful in motor neuron regeneration [ 69 ]. Endogenous small molecules with their function in embryonic development can also be used in in vitro methods to induce the differentiation of cells; for example, retinoic acid, which is responsible for patterning the nervous system in vivo [ 70 ], surprisingly induced retinal cell formation when the laboratory procedure involved hESCs [ 71 ].

The efficacy of differentiation factors depends on functional maturity, efficiency, and, finally, introducing produced cells to their in vivo equivalent. Topography, shear stress, and substrate rigidity are factors influencing the phenotype of future cells [ 72 ].

The control of biophysical and biochemical signals, the biophysical environment, and a proper guide of hESC differentiation are important factors in appropriately cultured stem cells.

Stem cell utilization and their manufacturing standards and culture systems

The European Medicines Agency and the Food and Drug Administration have set Good Manufacturing Practice (GMP) guidelines for safe and appropriate stem cell transplantation. In the past, protocols used for stem cell transplantation required animal-derived products [ 73 ].

The risk of introducing animal antigens or pathogens caused a restriction in their use. Due to such limitations, the technique required an obvious update [ 74 ]. Now, it is essential to use xeno-free equivalents when establishing cell lines that are derived from fresh embryos and cultured from human feeder cell lines [ 75 ]. In this method, it is crucial to replace any non-human materials with xeno-free equivalents [ 76 ].

NutriStem with LN-511, TeSR2 with human recombinant laminin (LN-511), and RegES with human foreskin fibroblasts (HFFs) are commonly used xeno-free culture systems [ 33 ]. There are many organizations and international initiatives, such as the National Stem Cell Bank, that provide stem cell lines for treatment or medical research [ 77 ].

Stem cell use in medicine

Stem cells have great potential to become one of the most important aspects of medicine. In addition to the fact that they play a large role in developing restorative medicine, their study reveals much information about the complex events that happen during human development.

The difference between a stem cell and a differentiated cell is reflected in the cells’ DNA. In the former cell, DNA is arranged loosely with working genes. When signals enter the cell and the differentiation process begins, genes that are no longer needed are shut down, but genes required for the specialized function will remain active. This process can be reversed, and it is known that such pluripotency can be achieved by interaction in gene sequences. Takahashi and Yamanaka [ 78 ] and Loh et al. [ 79 ] discovered that octamer-binding transcription factor 3 and 4 (Oct3/4), sex determining region Y (SRY)-box 2 and Nanog genes function as core transcription factors in maintaining pluripotency. Among them, Oct3/4 and Sox2 are essential for the generation of iPSCs.

Many serious medical conditions, such as birth defects or cancer, are caused by improper differentiation or cell division. Currently, several stem cell therapies are possible, among which are treatments for spinal cord injury, heart failure [ 80 ], retinal and macular degeneration [ 81 ], tendon ruptures, and diabetes type 1 [ 82 ]. Stem cell research can further help in better understanding stem cell physiology. This may result in finding new ways of treating currently incurable diseases.

Haematopoietic stem cell transplantation

Haematopoietic stem cells are important because they are by far the most thoroughly characterized tissue-specific stem cell; after all, they have been experimentally studied for more than 50 years. These stem cells appear to provide an accurate paradigm model system to study tissue-specific stem cells, and they have potential in regenerative medicine.

Multipotent haematopoietic stem cell (HSC) transplantation is currently the most popular stem cell therapy. Target cells are usually derived from the bone marrow, peripheral blood, or umbilical cord blood [ 83 ]. The procedure can be autologous (when the patient’s own cells are used), allogenic (when the stem cell comes from a donor), or syngeneic (from an identical twin). HSCs are responsible for the generation of all functional haematopoietic lineages in blood, including erythrocytes, leukocytes, and platelets. HSC transplantation solves problems that are caused by inappropriate functioning of the haematopoietic system, which includes diseases such as leukaemia and anaemia. However, when conventional sources of HSC are taken into consideration, there are some important limitations. First, there is a limited number of transplantable cells, and an efficient way of gathering them has not yet been found. There is also a problem with finding a fitting antigen-matched donor for transplantation, and viral contamination or any immunoreactions also cause a reduction in efficiency in conventional HSC transplantations. Haematopoietic transplantation should be reserved for patients with life-threatening diseases because it has a multifactorial character and can be a dangerous procedure. iPSC use is crucial in this procedure. The use of a patient’s own unspecialized somatic cells as stem cells provides the greatest immunological compatibility and significantly increases the success of the procedure.

Stem cells as a target for pharmacological testing

Stem cells can be used in new drug tests. Each experiment on living tissue can be performed safely on specific differentiated cells from pluripotent cells. If any undesirable effect appears, drug formulas can be changed until they reach a sufficient level of effectiveness. The drug can enter the pharmacological market without harming any live testers. However, to test the drugs properly, the conditions must be equal when comparing the effects of two drugs. To achieve this goal, researchers need to gain full control of the differentiation process to generate pure populations of differentiated cells.

Stem cells as an alternative for arthroplasty

One of the biggest fears of professional sportsmen is getting an injury, which most often signifies the end of their professional career. This applies especially to tendon injuries, which, due to current treatment options focusing either on conservative or surgical treatment, often do not provide acceptable outcomes. Problems with the tendons start with their regeneration capabilities. Instead of functionally regenerating after an injury, tendons merely heal by forming scar tissues that lack the functionality of healthy tissues. Factors that may cause this failed healing response include hypervascularization, deposition of calcific materials, pain, or swelling [ 84 ].

Additionally, in addition to problems with tendons, there is a high probability of acquiring a pathological condition of joints called osteoarthritis (OA) [ 85 ]. OA is common due to the avascular nature of articular cartilage and its low regenerative capabilities [ 86 ]. Although arthroplasty is currently a common procedure in treating OA, it is not ideal for younger patients because they can outlive the implant and will require several surgical procedures in the future. These are situations where stem cell therapy can help by stopping the onset of OA [ 87 ]. However, these procedures are not well developed, and the long-term maintenance of hyaline cartilage requires further research.

Osteonecrosis of the femoral hip (ONFH) is a refractory disease associated with the collapse of the femoral head and risk of hip arthroplasty in younger populations [ 88 ]. Although total hip arthroplasty (THA) is clinically successful, it is not ideal for young patients, mostly due to the limited lifetime of the prosthesis. An increasing number of clinical studies have evaluated the therapeutic effect of stem cells on ONFH. Most of the authors demonstrated positive outcomes, with reduced pain, improved function, or avoidance of THA [ 89 , 90 , 91 ].

Rejuvenation by cell programming

Ageing is a reversible epigenetic process. The first cell rejuvenation study was published in 2011 [ 92 ]. Cells from aged individuals have different transcriptional signatures, high levels of oxidative stress, dysfunctional mitochondria, and shorter telomeres than in young cells [ 93 ]. There is a hypothesis that when human or mouse adult somatic cells are reprogrammed to iPSCs, their epigenetic age is virtually reset to zero [ 94 ]. This was based on an epigenetic model, which explains that at the time of fertilization, all marks of parenteral ageing are erased from the zygote’s genome and its ageing clock is reset to zero [ 95 ].

In their study, Ocampo et al. [ 96 ] used Oct4, Sox2, Klf4, and C-myc genes (OSKM genes) and affected pancreas and skeletal muscle cells, which have poor regenerative capacity. Their procedure revealed that these genes can also be used for effective regenerative treatment [ 97 ]. The main challenge of their method was the need to employ an approach that does not use transgenic animals and does not require an indefinitely long application. The first clinical approach would be preventive, focused on stopping or slowing the ageing rate. Later, progressive rejuvenation of old individuals can be attempted. In the future, this method may raise some ethical issues, such as overpopulation, leading to lower availability of food and energy.

For now, it is important to learn how to implement cell reprogramming technology in non-transgenic elder animals and humans to erase marks of ageing without removing the epigenetic marks of cell identity.

Cell-based therapies

Stem cells can be induced to become a specific cell type that is required to repair damaged or destroyed tissues (Fig.  6 ). Currently, when the need for transplantable tissues and organs outweighs the possible supply, stem cells appear to be a perfect solution for the problem. The most common conditions that benefit from such therapy are macular degenerations [ 98 ], strokes [ 99 ], osteoarthritis [ 89 , 90 ], neurodegenerative diseases, and diabetes [ 100 ]. Due to this technique, it can become possible to generate healthy heart muscle cells and later transplant them to patients with heart disease.

Stem cell experiments on animals. These experiments are one of the many procedures that proved stem cells to be a crucial factor in future regenerative medicine

In the case of type 1 diabetes, insulin-producing cells in the pancreas are destroyed due to an autoimmunological reaction. As an alternative to transplantation therapy, it can be possible to induce stem cells to differentiate into insulin-producing cells [ 101 ].

Stem cells and tissue banks

iPS cells with their theoretically unlimited propagation and differentiation abilities are attractive for the present and future sciences. They can be stored in a tissue bank to be an essential source of human tissue used for medical examination. The problem with conventional differentiated tissue cells held in the laboratory is that their propagation features diminish after time. This does not occur in iPSCs.

The umbilical cord is known to be rich in mesenchymal stem cells. Due to its cryopreservation immediately after birth, its stem cells can be successfully stored and used in therapies to prevent the future life-threatening diseases of a given patient.

Stem cells of human exfoliated deciduous teeth (SHED) found in exfoliated deciduous teeth has the ability to develop into more types of body tissues than other stem cells [ 102 ] (Table  1 ). Techniques of their collection, isolation, and storage are simple and non-invasive. Among the advantages of banking, SHED cells are:

Guaranteed donor-match autologous transplant that causes no immune reaction and rejection of cells [ 103 ]

Simple and painless for both child and parent

Less than one third of the cost of cord blood storage

Not subject to the same ethical concerns as embryonic stem cells [ 104 ]

In contrast to cord blood stem cells, SHED cells are able to regenerate into solid tissues such as connective, neural, dental, or bone tissue [ 105 , 106 ]

SHED can be useful for close relatives of the donor

Fertility diseases

In 2011, two researchers, Katsuhiko Hayashi et al. [ 107 ], showed in an experiment on mice that it is possible to form sperm from iPSCs. They succeeded in delivering healthy and fertile pups in infertile mice. The experiment was also successful for female mice, where iPSCs formed fully functional eggs .

Young adults at risk of losing their spermatogonial stem cells (SSC), mostly cancer patients, are the main target group that can benefit from testicular tissue cryopreservation and autotransplantation. Effective freezing methods for adult and pre-pubertal testicular tissue are available [ 108 ].

Qiuwan et al. [ 109 ] provided important evidence that human amniotic epithelial cell (hAEC) transplantation could effectively improve ovarian function by inhibiting cell apoptosis and reducing inflammation in injured ovarian tissue of mice, and it could be a promising strategy for the management of premature ovarian failure or insufficiency in female cancer survivors.

For now, reaching successful infertility treatments in humans appears to be only a matter of time, but there are several challenges to overcome. First, the process needs to have high efficiency; second, the chances of forming tumours instead of eggs or sperm must be maximally reduced. The last barrier is how to mature human sperm and eggs in the lab without transplanting them to in vivo conditions, which could cause either a tumour risk or an invasive procedure.

Therapy for incurable neurodegenerative diseases

Thanks to stem cell therapy, it is possible not only to delay the progression of incurable neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease (AD), and Huntington disease, but also, most importantly, to remove the source of the problem. In neuroscience, the discovery of neural stem cells (NSCs) has nullified the previous idea that adult CNS were not capable of neurogenesis [ 110 , 111 ]. Neural stem cells are capable of improving cognitive function in preclinical rodent models of AD [ 112 , 113 , 114 ]. Awe et al. [ 115 ] clinically derived relevant human iPSCs from skin punch biopsies to develop a neural stem cell-based approach for treating AD. Neuronal degeneration in Parkinson’s disease (PD) is focal, and dopaminergic neurons can be efficiently generated from hESCs. PD is an ideal disease for iPSC-based cell therapy [ 116 ]. However, this therapy is still in an experimental phase ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539501 /). Brain tissue from aborted foetuses was used on patients with Parkinson’s disease [ 117 ]. Although the results were not uniform, they showed that therapies with pure stem cells are an important and achievable therapy.

Stem cell use in dentistry

Teeth represent a very challenging material for regenerative medicine. They are difficult to recreate because of their function in aspects such as articulation, mastication, or aesthetics due to their complicated structure. Currently, there is a chance for stem cells to become more widely used than synthetic materials. Teeth have a large advantage of being the most natural and non-invasive source of stem cells.

For now, without the use of stem cells, the most common periodontological treatments are either growth factors, grafts, or surgery. For example, there are stem cells in periodontal ligament [ 118 , 119 ], which are capable of differentiating into osteoblasts or cementoblasts, and their functions were also assessed in neural cells [ 120 ]. Tissue engineering is a successful method for treating periodontal diseases. Stem cells of the root apical areas are able to recreate periodontal ligament. One of the possible methods of tissue engineering in periodontology is gene therapy performed using adenoviruses-containing growth factors [ 121 ].

As a result of animal studies, dentin regeneration is an effective process that results in the formation of dentin bridges [ 122 ].

Enamel is more difficult to regenerate than dentin. After the differentiation of ameloblastoma cells into the enamel, the former is destroyed, and reparation is impossible. Medical studies have succeeded in differentiating bone marrow stem cells into ameloblastoma [ 123 ].

Healthy dental tissue has a high amount of regular stem cells, although this number is reduced when tissue is either traumatized or inflamed [ 124 ]. There are several dental stem cell groups that can be isolated (Fig.  7 ).

Localization of stem cells in dental tissues. Dental pulp stem cells (DPSCs) and human deciduous teeth stem cells (SHED) are located in the dental pulp. Periodontal ligaments stem cells are located in the periodontal ligament. Apical papilla consists of stem cells from the apical papilla (SCAP)

Dental pulp stem cell (DPSC)

These were the first dental stem cells isolated from the human dental pulp, which were [ 125 ] located inside dental pulp (Table  2 ). They have osteogenic and chondrogenic potential. Mesenchymal stem cells (MSCs) of the dental pulp, when isolated, appear highly clonogenic; they can be isolated from adult tissue (e.g. bone marrow, adipose tissue) and foetal (e.g. umbilical cord) [ 126 ] tissue, and they are able to differentiate densely [ 127 ]. MSCs differentiate into odontoblast-like cells and osteoblasts to form dentin and bone. Their best source locations are the third molars [ 125 ]. DPSCs are the most useful dental source of tissue engineering due to their easy surgical accessibility, cryopreservation possibility, increased production of dentin tissues compared to non-dental stem cells, and their anti-inflammatory abilities. These cells have the potential to be a source for maxillofacial and orthopaedic reconstructions or reconstructions even beyond the oral cavity. DPSCs are able to generate all structures of the developed tooth [ 128 ]. In particular, beneficial results in the use of DPSCs may be achieved when combined with other new therapies, such as periodontal tissue photobiomodulation (laser stimulation), which is an efficient technique in the stimulation of proliferation and differentiation into distinct cell types [ 129 ]. DPSCs can be induced to form neural cells to help treat neurological deficits.

Stem cells of human exfoliated deciduous teeth (SHED) have a faster rate of proliferation than DPSCs and differentiate into an even greater number of cells, e.g. other mesenchymal and non-mesenchymal stem cell derivatives, such as neural cells [ 130 ]. These cells possess one major disadvantage: they form a non-complete dentin/pulp-like complex in vivo. SHED do not undergo the same ethical concerns as embryonic stem cells. Both DPSCs and SHED are able to form bone-like tissues in vivo [ 131 ] and can be used for periodontal, dentin, or pulp regeneration. DPSCs and SHED can be used in treating, for example, neural deficits [ 132 ]. DPSCs alone were tested and successfully applied for alveolar bone and mandible reconstruction [ 133 ].

Periodontal ligament stem cells (PDLSCs)

These cells are used in periodontal ligament or cementum tissue regeneration. They can differentiate into mesenchymal cell lineages to produce collagen-forming cells, adipocytes, cementum tissue, Sharpey’s fibres, and osteoblast-like cells in vitro. PDLSCs exist both on the root and alveolar bone surfaces; however, on the latter, these cells have better differentiation abilities than on the former [ 134 ]. PDLSCs have become the first treatment for periodontal regeneration therapy because of their safety and efficiency [ 135 , 136 ].

Stem cells from apical papilla (SCAP)

These cells are mesenchymal structures located within immature roots. They are isolated from human immature permanent apical papilla. SCAP are the source of odontoblasts and cause apexogenesis. These stem cells can be induced in vitro to form odontoblast-like cells, neuron-like cells, or adipocytes. SCAP have a higher capacity of proliferation than DPSCs, which makes them a better choice for tissue regeneration [ 137 , 138 ].

Dental follicle stem cells (DFCs)

These cells are loose connective tissues surrounding the developing tooth germ. DFCs contain cells that can differentiate into cementoblasts, osteoblasts, and periodontal ligament cells [ 139 , 140 ]. Additionally, these cells proliferate after even more than 30 passages [ 141 ]. DFCs are most commonly extracted from the sac of a third molar. When DFCs are combined with a treated dentin matrix, they can form a root-like tissue with a pulp-dentin complex and eventually form tooth roots [ 141 ]. When DFC sheets are induced by Hertwig’s epithelial root sheath cells, they can produce periodontal tissue; thus, DFCs represent a very promising material for tooth regeneration [ 142 ].

Pulp regeneration in endodontics

Dental pulp stem cells can differentiate into odontoblasts. There are few methods that enable the regeneration of the pulp.

The first is an ex vivo method. Proper stem cells are grown on a scaffold before they are implanted into the root channel [ 143 ].

The second is an in vivo method. This method focuses on injecting stem cells into disinfected root channels after the opening of the in vivo apex. Additionally, the use of a scaffold is necessary to prevent the movement of cells towards other tissues. For now, only pulp-like structures have been created successfully.

Methods of placing stem cells into the root channel constitute are either soft scaffolding [ 144 ] or the application of stem cells in apexogenesis or apexification. Immature teeth are the best source [ 145 ]. Nerve and blood vessel network regeneration are extremely vital to keep pulp tissue healthy.

The potential of dental stem cells is mainly regarding the regeneration of damaged dentin and pulp or the repair of any perforations; in the future, it appears to be even possible to generate the whole tooth. Such an immense success would lead to the gradual replacement of implant treatments. Mandibulary and maxillary defects can be one of the most complicated dental problems for stem cells to address.

Acquiring non-dental tissue cells by dental stem cell differentiation

In 2013, it was reported that it is possible to grow teeth from stem cells obtained extra-orally, e.g. from urine [ 146 ]. Pluripotent stem cells derived from human urine were induced and generated tooth-like structures. The physical properties of the structures were similar to natural ones except for hardness [ 127 ]. Nonetheless, it appears to be a very promising technique because it is non-invasive and relatively low-cost, and somatic cells can be used instead of embryonic cells. More importantly, stem cells derived from urine did not form any tumours, and the use of autologous cells reduces the chances of rejection [ 147 ].

Use of graphene in stem cell therapy

Over recent years, graphene and its derivatives have been increasingly used as scaffold materials to mediate stem cell growth and differentiation [ 148 ]. Both graphene and graphene oxide (GO) represent high in-plane stiffness [ 149 ]. Because graphene has carbon and aromatic network, it works either covalently or non-covalently with biomolecules; in addition to its superior mechanical properties, graphene offers versatile chemistry. Graphene exhibits biocompatibility with cells and their proper adhesion. It also tested positively for enhancing the proliferation or differentiation of stem cells [ 148 ]. After positive experiments, graphene revealed great potential as a scaffold and guide for specific lineages of stem cell differentiation [ 150 ]. Graphene has been successfully used in the transplantation of hMSCs and their guided differentiation to specific cells. The acceleration skills of graphene differentiation and division were also investigated. It was discovered that graphene can serve as a platform with increased adhesion for both growth factors and differentiation chemicals. It was also discovered that π-π binding was responsible for increased adhesion and played a crucial role in inducing hMSC differentiation [ 150 ].

Therapeutic potential of extracellular vesicle-based therapies

Extracellular vesicles (EVs) can be released by virtually every cell of an organism, including stem cells [ 151 ], and are involved in intercellular communication through the delivery of their mRNAs, lipids, and proteins. As Oh et al. [ 152 ] prove, stem cells, together with their paracrine factors—exosomes—can become potential therapeutics in the treatment of, e.g. skin ageing. Exosomes are small membrane vesicles secreted by most cells (30–120 nm in diameter) [ 153 ]. When endosomes fuse with the plasma membrane, they become exosomes that have messenger RNAs (mRNAs) and microRNAs (miRNAs), some classes of non-coding RNAs (IncRNAs) and several proteins that originate from the host cell [ 154 ]. IncRNAs can bind to specific loci and create epigenetic regulators, which leads to the formation of epigenetic modifications in recipient cells. Because of this feature, exosomes are believed to be implicated in cell-to-cell communication and the progression of diseases such as cancer [ 155 ]. Recently, many studies have also shown the therapeutic use of exosomes derived from stem cells, e.g. skin damage and renal or lung injuries [ 156 ].

In skin ageing, the most important factor is exposure to UV light, called “photoageing” [ 157 ], which causes extrinsic skin damage, characterized by dryness, roughness, irregular pigmentation, lesions, and skin cancers. In intrinsic skin ageing, on the other hand, the loss of elasticity is a characteristic feature. The skin dermis consists of fibroblasts, which are responsible for the synthesis of crucial skin elements, such as procollagen or elastic fibres. These elements form either basic framework extracellular matrix constituents of the skin dermis or play a major role in tissue elasticity. Fibroblast efficiency and abundance decrease with ageing [ 158 ]. Stem cells can promote the proliferation of dermal fibroblasts by secreting cytokines such as platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), and basic fibroblast growth factor. Huh et al. [ 159 ] mentioned that a medium of human amniotic fluid-derived stem cells (hAFSC) positively affected skin regeneration after longwave UV-induced (UVA, 315–400 nm) photoageing by increasing the proliferation and migration of dermal fibroblasts. It was discovered that, in addition to the induction of fibroblast physiology, hAFSC transplantation also improved diseases in cases of renal pathology, various cancers, or stroke [ 160 , 161 ].

Oh [ 162 ] also presented another option for the treatment of skin wounds, either caused by physical damage or due to diabetic ulcers. Induced pluripotent stem cell-conditioned medium (iPSC-CM) without any animal-derived components induced dermal fibroblast proliferation and migration.

Natural cutaneous wound healing is divided into three steps: haemostasis/inflammation, proliferation, and remodelling. During the crucial step of proliferation, fibroblasts migrate and increase in number, indicating that it is a critical step in skin repair, and factors such as iPSC-CM that impact it can improve the whole cutaneous wound healing process. Paracrine actions performed by iPSCs are also important for this therapeutic effect [ 163 ]. These actions result in the secretion of cytokines such as TGF-β, interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and basic fibroblast growth factor (bFGF). Bae et al. [ 164 ] mentioned that TGF-β induced the migration of keratinocytes. It was also demonstrated that iPSC factors can enhance skin wound healing in vivo and in vitro when Zhou et al. [ 165 ] enhanced wound healing, even after carbon dioxide laser resurfacing in an in vivo study.

Peng et al. [ 166 ] investigated the effects of EVs derived from hESCs on in vitro cultured retinal glial, progenitor Müller cells, which are known to differentiate into retinal neurons. EVs appear heterogeneous in size and can be internalized by cultured Müller cells, and their proteins are involved in the induction and maintenance of stem cell pluripotency. These stem cell-derived vesicles were responsible for the neuronal trans-differentiation of cultured Müller cells exposed to them. However, the research article points out that the procedure was accomplished only on in vitro acquired retina.

Challenges concerning stem cell therapy

Although stem cells appear to be an ideal solution for medicine, there are still many obstacles that need to be overcome in the future. One of the first problems is ethical concern.

The most common pluripotent stem cells are ESCs. Therapies concerning their use at the beginning were, and still are, the source of ethical conflicts. The reason behind it started when, in 1998, scientists discovered the possibility of removing ESCs from human embryos. Stem cell therapy appeared to be very effective in treating many, even previously incurable, diseases. The problem was that when scientists isolated ESCs in the lab, the embryo, which had potential for becoming a human, was destroyed (Fig.  8 ). Because of this, scientists, seeing a large potential in this treatment method, focused their efforts on making it possible to isolate stem cells without endangering their source—the embryo.

Use of inner cell mass pluripotent stem cells and their stimulation to differentiate into desired cell types

For now, while hESCs still remain an ethically debatable source of cells, they are potentially powerful tools to be used for therapeutic applications of tissue regeneration. Because of the complexity of stem cell control systems, there is still much to be learned through observations in vitro. For stem cells to become a popular and widely accessible procedure, tumour risk must be assessed. The second problem is to achieve successful immunological tolerance between stem cells and the patient’s body. For now, one of the best ideas is to use the patient’s own cells and devolve them into their pluripotent stage of development.

New cells need to have the ability to fully replace lost or malfunctioning natural cells. Additionally, there is a concern about the possibility of obtaining stem cells without the risk of morbidity or pain for either the patient or the donor. Uncontrolled proliferation and differentiation of cells after implementation must also be assessed before its use in a wide variety of regenerative procedures on living patients [ 167 ].

One of the arguments that limit the use of iPSCs is their infamous role in tumourigenicity. There is a risk that the expression of oncogenes may increase when cells are being reprogrammed. In 2008, a technique was discovered that allowed scientists to remove oncogenes after a cell achieved pluripotency, although it is not efficient yet and takes a longer amount of time. The process of reprogramming may be enhanced by deletion of the tumour suppressor gene p53, but this gene also acts as a key regulator of cancer, which makes it impossible to remove in order to avoid more mutations in the reprogrammed cell. The low efficiency of the process is another problem, which is progressively becoming reduced with each year. At first, the rate of somatic cell reprogramming in Yamanaka’s study was up to 0.1%. The use of transcription factors creates a risk of genomic insertion and further mutation of the target cell genome. For now, the only ethically acceptable operation is an injection of hESCs into mouse embryos in the case of pluripotency evaluation [ 168 ].

Stem cell obstacles in the future

Pioneering scientific and medical advances always have to be carefully policed in order to make sure they are both ethical and safe. Because stem cell therapy already has a large impact on many aspects of life, it should not be treated differently.

Currently, there are several challenges concerning stem cells. First, the most important one is about fully understanding the mechanism by which stem cells function first in animal models. This step cannot be avoided. For the widespread, global acceptance of the procedure, fear of the unknown is the greatest challenge to overcome.

The efficiency of stem cell-directed differentiation must be improved to make stem cells more reliable and trustworthy for a regular patient. The scale of the procedure is another challenge. Future stem cell therapies may be a significant obstacle. Transplanting new, fully functional organs made by stem cell therapy would require the creation of millions of working and biologically accurate cooperating cells. Bringing such complicated procedures into general, widespread regenerative medicine will require interdisciplinary and international collaboration.

The identification and proper isolation of stem cells from a patient’s tissues is another challenge. Immunological rejection is a major barrier to successful stem cell transplantation. With certain types of stem cells and procedures, the immune system may recognize transplanted cells as foreign bodies, triggering an immune reaction resulting in transplant or cell rejection.

One of the ideas that can make stem cells a “failsafe” is about implementing a self-destruct option if they become dangerous. Further development and versatility of stem cells may cause reduction of treatment costs for people suffering from currently incurable diseases. When facing certain organ failure, instead of undergoing extraordinarily expensive drug treatment, the patient would be able to utilize stem cell therapy. The effect of a successful operation would be immediate, and the patient would avoid chronic pharmacological treatment and its inevitable side effects.

Although these challenges facing stem cell science can be overwhelming, the field is making great advances each day. Stem cell therapy is already available for treating several diseases and conditions. Their impact on future medicine appears to be significant.

After several decades of experiments, stem cell therapy is becoming a magnificent game changer for medicine. With each experiment, the capabilities of stem cells are growing, although there are still many obstacles to overcome. Regardless, the influence of stem cells in regenerative medicine and transplantology is immense. Currently, untreatable neurodegenerative diseases have the possibility of becoming treatable with stem cell therapy. Induced pluripotency enables the use of a patient’s own cells. Tissue banks are becoming increasingly popular, as they gather cells that are the source of regenerative medicine in a struggle against present and future diseases. With stem cell therapy and all its regenerative benefits, we are better able to prolong human life than at any time in history.

Abbreviations

Basic fibroblast growth factor

Bone morphogenic proteins

Dental follicle stem cells

Dental pulp stem cells

Embryonic bodies

Embryonic stem cells

Fibroblast growth factors

Good Manufacturing Practice

Graphene oxide

Human amniotic fluid-derived stem cells

Human embryonic stem cells

Human foreskin fibroblasts

Inner cell mass

Non-coding RNA

Induced pluripotent stem cells

In vitro fertilization

Knockout serum replacement

Leukaemia inhibitory factor

Monocyte chemotactic protein-1

Fibroblasts

Messenger RNA

Mesenchymal stem cells of dental pulp

Myogenic differentiation

Osteoarthritis

Octamer-binding transcription factor 3 and 4

Platelet-derived growth factor

Platelet-derived growth factor-AA

Periodontal ligament stem cells

Rho-associated protein kinase

Stem cells from apical papilla

Stem cells of human exfoliated deciduous teeth

Synthetic Serum Substitute

Trophectoderm

Vascular endothelial growth factor

Transforming growth factors

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Zakrzewski, W., Dobrzyński, M., Szymonowicz, M. et al. Stem cells: past, present, and future. Stem Cell Res Ther 10 , 68 (2019). https://doi.org/10.1186/s13287-019-1165-5

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Lupus patient Katherine Hammons comforts fellow patient Margaret Laperle, both treated with stem cells from their own bone marrow. Stem cells could launch a new era of regenerative medicine, curing deadly diseases with custom-made tissues and organs.

The Stem Cell Divide

In the beginning, one cell becomes two, and two become four. Being fruitful, they multiply into a ball of many cells, a shimmering sphere of human potential. Scientists have long dreamed of plucking those naive cells from a young human embryo and coaxing them to perform, in sterile isolation, the everyday miracle they perform in wombs: transforming into all the 200 or so kinds of cells that constitute a human body. Liver cells. Brain cells. Skin, bone, and nerve.

The dream is to launch a medical revolution in which ailing organs and tissues might be repaired—not with crude mechanical devices like insulin pumps and titanium joints but with living, homegrown replacements. It would be the dawn of a new era of regenerative medicine, one of the holy grails of modern biology.

Revolutions, alas, are almost always messy. So when James Thomson, a soft-spoken scientist at the University of Wisconsin in Madison, reported in November 1998 that he had succeeded in removing cells from spare embryos at fertility clinics and establishing the world's first human embryonic stem cell line, he and other scientists got a lot more than they bargained for. It was the kind of discovery that under most circumstances would have blossomed into a major federal research enterprise. Instead the discovery was quickly engulfed in the turbulent waters of religion and politics. In church pews, congressional hearing rooms, and finally the Oval Office, people wanted to know: Where were the needed embryos going to come from, and how many would have to be destroyed to treat the millions of patients who might be helped? Before long, countries around the world were embroiled in the debate.

Most alarmed have been people who see embryos as fully vested, vulnerable members of society, and who decry the harvesting of cells from embryos as akin to cannibalism. They warn of a brave new world of "embryo farms" and "cloning mills" for the cultivation of human spare parts. And they argue that scientists can achieve the same results using adult stem cells— immature cells found in bone marrow and other organs in adult human beings, as well as in umbilical cords normally discarded at birth.

Advocates counter that adult stem cells, useful as they may be for some diseases, have thus far proved incapable of producing the full range of cell types that embryonic stem cells can. They point out that fertility clinic freezers worldwide are bulging with thousands of unwanted embryos slated for disposal. Those embryos are each smaller than the period at the end of this sentence. They have no identifying features or hints of a nervous system. If parents agree to donate them, supporters say, it would be unethical not to do so in the quest to cure people of disease.

Few question the medical promise of embryonic stem cells. Consider the biggest United States killer of all: heart disease. Embryonic stem cells can be trained to grow into heart muscle cells that, even in a laboratory dish, clump together and pulse in spooky unison. And when those heart cells have been injected into mice and pigs with heart disease, they've filled in for injured or dead cells and sped recovery. Similar studies have suggested stem cells' potential for conditions such as diabetes and spinal cord injury.

Critics point to worrisome animal research showing that embryonic stem cells sometimes grow into tumors or morph into unwanted kinds of tissues—possibly forming, for example, dangerous bits of bone in those hearts they are supposedly repairing. But supporters respond that such problems are rare and a lot has recently been learned about how to prevent them.

The arguments go back and forth, but policymakers and governments aren't waiting for answers. Some countries, such as Germany, worried about a slippery slope toward unethical human experimentation, have already prohibited some types of stem cell research. Others, like the U.S., have imposed severe limits on government funding but have left the private sector to do what it wants. Still others, such as the U.K., China, Korea, and Singapore, have set out to become the epicenters of stem cell research, providing money as well as ethical oversight to encourage the field within carefully drawn bounds.

In such varied political climates, scientists around the globe are racing to see which techniques will produce treatments soonest. Their approaches vary, but on one point, all seem to agree: How humanity handles its control over the mysteries of embryo development will say a lot about who we are and what we're becoming.

For more than half   of his seven years, Cedric Seldon has been fighting leukemia. Now having run out of options, he is about to become a biomedical pioneer—one of about 600 Americans last year to be treated with an umbilical cord blood transplant.

Cord blood transplants—considered an adult stem cell therapy because the cells come from infants, not embryos—have been performed since 1988. Like bone marrow, which doctors have been transplanting since 1968, cord blood is richly endowed with a kind of stem cell that gives rise to oxygen-carrying red blood cells, disease-fighting white blood cells, and other parts of the blood and immune systems. Unlike a simple blood transfusion, which provides a batch of cells destined to die in a few months, the stem cells found in bone marrow and cord blood can—if all goes well—burrow into a person's bones, settle there for good, and generate fresh blood and immune cells for a lifetime.

Propped on a hospital bed at Duke University Medical Center, Cedric works his thumbs furiously against a pair of joysticks that control a careening vehicle in a Starsky and Hutch video game. "Hang on, Hutch!" older brother Daniel shouts from the bedside, as a nurse, ignoring the screeching tires and gunshots, sorts through a jumble of tubes and hangs a bag of cord blood cells from a chrome pole. Just an hour ago I watched those cells being thawed and spun in a centrifuge—awakening them for the first time since 2001, when they were extracted from the umbilical cord of a newborn and donated by her parents to a cell bank at Duke. The time has come for those cells to prove their reputed mettle.

For days Cedric has endured walloping doses of chemotherapy and radiation in a last-ditch effort to kill every cancer cell in his body. Such powerful therapy has the dangerous side-effect of destroying patients' blood-making stem cells, and so is never applied unless replacement stem cells are available. A search of every bone marrow bank in the country had found no match for Cedric's genetic profile, and it was beginning to look as if he'd run out of time. Then a computer search turned up the frozen cord blood cells at Duke—not a perfect match, but close enough to justify trying.

"Ready?" the nurse asks. Mom and dad, who have spent hours in prayer, nod yes, and a line of crimson wends its way down the tube, bringing the first of about 600 million cells into the boy's body. The video game's sound effects seem to fade behind a muffling curtain of suspense. Although Cedric's balloon-laden room is buoyant with optimism, success is far from certain.

"Grow, cells, grow," Cedric's dad whispers.

His mom's eyes are misty. I ask what she sees when she looks at the cells trickling into her son.

"Life," she says. "It's his rebirth."

It will be a month before tests reveal whether Cedric's new cells have taken root, but in a way he's lucky. All he needs is a new blood supply and immune system, which are relatively easy to re-create. Countless other patients are desperate to regenerate more than that. Diabetics need new insulin-producing cells. Heart attack victims could benefit from new cardiac cells. Paraplegics might even walk again if the nerves in their spinal cords could regrow.

In a brightly lit laboratory halfway across the country from Cedric's hospital room, three teams of scientists at the University of Wisconsin in Madison are learning how to grow the embryonic stem cells that might make such cures possible. Unlike adult stem cells, which appear to have limited repertoires, embryonic stem cells are pluripotent—they can become virtually every kind of human cell. The cells being nurtured here are direct descendants of the ones James Thomson isolated seven years ago.

For years Thomson and his colleagues have been expanding some of those original stem cells into what are called stem cell lines—colonies of millions of pluripotent cells that keep proliferating without differentiating into specific cell types. The scientists have repeatedly moved each cell's offspring to less crowded laboratory dishes, allowing them to divide again and again. And while they worked, the nation struggled to get a handle on the morality of what they were doing.

It took almost two years for President Bill Clinton's administration to devise ethics guidelines and a system for funding the new field. George W. Bush's ascension prevented that plan from going into effect, and all eyes turned to the conservative Texan to see what he would do. On August 9, 2001, Bush announced that federal funds could be used to study embryonic stem cells. But to prevent taxpayers from becoming complicit in the destruction of human embryos, that money could be used only to study the stem cell lines already in the works as of that date—a number that, for practical reasons, has resulted in about two dozen usable lines. Those wishing to work with any of the more than a hundred stem cell lines created after that date can do so only with private funding.

Every month scientists from around the world arrive in Madison to take a three-day course in how to grow those approved cells. To watch what they must go through to keep the cells happy is to appreciate why many feel hobbled by the Bush doctrine. For one thing—and for reasons not fully understood—the surest way to keep these cells alive is to place them on a layer of other cells taken from mouse embryos, a time-consuming requirement. Hunched over lab benches, deftly handling forceps and pipettes with blue latex gloves, each scientist in Madison spends the better half of a day dissecting a pregnant mouse, removing its uterus, and prying loose a string of embryos that look like little red peas in a pod. They then wash them, mash them, tease apart their cells, and get them growing in lab dishes. The result is a hormone-rich carpet of mouse cells upon which a few human embryonic stem cells are finally placed. There they live like pampered pashas.

If their scientist-servants don't feed them fresh liquid nutrients at least once a day, the cells die of starvation. If each colony is not split in half each week, it dies from overcrowding. And if a new layer of mouse cells is not prepared and provided every two weeks, the stem cells grow into weird and useless masses that finally die. By contrast, scientists working with private money have been developing embryonic stem cell lines that are hardier, less demanding, and not dependent on mouse cells. Bypassing the use of mouse cells is not only easier, but it also eliminates the risk that therapeutic stem cells might carry rodent viruses, thereby potentially speeding their approval for testing in humans.

Here in the Madison lab, scientists grumble about how fragile the precious colonies are. "They're hard to get to know," concedes Leann Crandall, one of the course's instructors and a co-author of the 85-page manual on their care and feeding. "But once you get to know them, you love them. You can't help it. They're so great. I see so many good things coming from them."

A few American scientists are finding it is easier to indulge their enthusiasm for stem cells overseas. Scores of new embryonic stem cell lines have now been created outside the U.S., and many countries are aggressively seeking to spur the development of therapies using these cells, raising a delicate question: Can the nation in which embryonic stem cells were discovered maintain its initial research lead?

"I know a lot of people back in the U.S. who would like to move into embryonic stem cell work but who won't because of the political uncertainties," says Stephen Minger, director of the Stem Cell Biology Laboratory at King's College in London, speaking to me in his cramped and cluttered office. "I think the United States is in real danger of being left behind."

Minger could be right. He is one of at least two high-profile stem cell scientists to move from the U.S. to England in the past few years, something less than a brain drain but a signal, perhaps, of bubbling discontent.

The research climate is good here, says Minger. In 2003 his team became the first in the U.K. to grow colonies of human embryonic stem cells, and his nine-person staff is poised to nearly double. He's developing new growth culture systems that won't rely on potentially infectious mouse cells. He's also figuring out how to make stem cells morph into cardiac, neural, pancreatic, and retinal cells and preparing to test those cells in animals. And in stark contrast to how things are done in the U.S., Minger says, he's doing all this with government support—and oversight.

The Human Fertilisation and Embryology Authority (HFEA), the government agency that has long overseen U.K. fertility clinics, is now also regulating the country's embryonic stem cell research. In closed-door meetings a committee of 18 people appointed by the National Health Service considers all requests to conduct research using embryos. The committee includes scientists, ethicists, lawyers, and clergy, but the majority are lay people representing the public.

To an American accustomed to high security and protesters at venues dealing regularly with embryo research, the most striking thing about the HFEA's headquarters in downtown London is its ordinariness. The office, a standard-issue warren of cubicles and metal filing cabinets, is on the second floor of a building that also houses the agency that deals with bankruptcy. I ask Ross Thacker, a research officer at the authority, whether the HFEA is regularly in need of yellow police tape to keep protesters at bay.

"Now that you mention it," he says, "there was a placard holder outside this morning …"

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"… but he was protesting something about the insolvency office."

Thacker politely refrains from criticizing U.S. policy on embryo research, but he clearly takes pride in the orderliness of the British system. The committee has approved about a dozen requests to create stem cell lines in the past 18 months, increasing the number of projects to 35. Most were relatively routine—until a strong-willed fertility doctor named Alison Murdoch decided to ask for permission to do something nobody had done before: create cloned human embryos as sources of stem cells.

As controversial as embryonic stem cell research can be, cloning embryos to produce those stem cells is even thornier. Much of the world became familiar with cloning in 1997, when scientists announced they'd cloned a sheep named Dolly. The process involves creating an animal not from egg and sperm but by placing the nucleus of a cell inside an egg that's had its nucleus removed. It's since been used to replicate mice, rabbits, cats, and cattle, among others.

As in many other countries and a few U.S. states, it's illegal in the U.K. to create cloned human babies (called reproductive cloning), because of concerns that clones may be biologically abnormal and because of ethical issues surrounding the creation of children who would be genetic replicas of their one-and-only "parent."

In 2001 the British Parliament made it legal to create cloned human embryos—as opposed to babies—for use in medical research (called therapeutic cloning). Still, no one on the HFEA was completely comfortable with the idea. The fear was that some rogue scientist would take the work a step further, gestate the embryo in a woman's womb, and make the birth announcement that no one wanted to hear.

But Murdoch, of the University of Newcastle upon Tyne, made a compelling case. If replacement tissues grown from stem cells bore the patient's exact genetic fingerprint, they would be less likely to be rejected by a patient's immune system, she told the committee. And what better way to get such a match than to derive the cells from an embryo cloned from the patient's own DNA? Disease research could also benefit, she said. Imagine an embryo—and its stem cells—cloned from a person with Lou Gehrig's disease, a fatal genetic disorder that affects nerves and muscles. Scientists might learn quite a bit, she argued, by watching how the disease damages nerve and muscle cells grown from those stem cells, and then testing various drugs on them. It's the kind of experiment that could never be done in a person with the disease.

The HFEA deliberated for five months before giving Murdoch permission to make human embryo clones in her lab at the Centre for Life in Newcastle, a sprawling neon-illuminated complex of buildings that strikes a decidedly modern note in the aging industrial hub. But there was a catch: It takes an egg to make a clone. And under the terms of HFEA approval, Murdoch is allowed to use only those eggs being disposed of by the center's fertility clinic after they failed to fertilize when mixed with sperm.

It's not a perfect arrangement, Murdoch says. After all, eggs that have failed to fertilize are almost by definition of poor quality. "They're not brilliant," she says of the eggs. "But the U.K. has decided at the moment that these are the most ethical sort to use. So that's really all we can work with." As of April the group hadn't managed to clone any embryos, despite numerous attempts.

No such obstacle faced Woo-Suk Hwang and his colleagues at Seoul National University in February 2004 when they became the world's first to clone human embryos and extract stem cells from them. The South Korean government allows research on human embryos made from healthy eggs—in this case, donated by 16 women who took egg-ripening hormones.

Cloning is an arduous process that requires great patience and almost always ends in failure as cells burst, tear, or suffer damage to their DNA, but the Koreans are expert cloners, their skills sharpened in the country's state-funded livestock-cloning enterprise. In Hwang's lab alone, technicians produce more than 700 cloned pig or cattle embryos every day, seven days a week, in a quest to produce livestock with precise genetic traits. "There is no holiday in our lab," Hwang told me with a smile.

But there is something else that gives Koreans an edge over other would-be cloners, Hwang says. "As you know, Asian countries use chopsticks, but only the Koreans use steel chopsticks," he explains. "The steel ones are the most difficult to use. Very slippery." I look at him, trying to tell if he's kidding. A lifetime of using steel chopsticks makes Koreans better at manipulating tiny eggs? "This is not simply a joke," he says.

Time will tell whether such skill will be enough to keep Korea in the lead as other countries turn to cloning as a source of stem cells. The competition will be tough. China has pioneered a potentially groundbreaking technique that produces cloned human embryos by mixing human skin cells with the eggs of rabbits, which are more easily obtained than human eggs. A few privately funded researchers in the U.S. are also pursuing therapeutic cloning.

Yet the biggest   competition in the international race to develop stem cell therapies may ultimately come from one of the smallest of countries—a tiny nation committed to becoming a stem cell superpower. To find that place, one need only track the migration patterns of top scientists who've been wooed there from the U.S., Australia, even the U.K. Where they've been landing, it turns out, is Singapore.

Amid the scores of small, botanically rich but barely inhabited islands in the South China Sea, Singapore stands out like a post-modern mirage. The towering laboratory buildings of its Biopolis were created in 2001 to jumpstart Singapore's biotechnology industry. Like a scene from a science fiction story, it features futuristic glass-and-metal buildings with names like Matrix, Proteos, and Chromos, connected by skywalks that facilitate exchanges among researchers.

Academic grants, corporate development money, laws that ban reproductive cloning but allow therapeutic cloning, and a science-savvy workforce are among the lures attracting stem cell researchers and entrepreneurs. Even Alan Colman—the renowned cloning expert who was part of the team that created Dolly, the cloned sheep—has taken leave of his home in the U.K. and become the chief executive of ES Cell International, one of a handful of major stem cell research companies blossoming in Singapore's fertile environs.

"You don't have to fly from New York to San Diego to see what's going on in other labs," says Robert Klupacs, the firm's previous CEO. "You just walk across the street. Because Singapore is small, things can happen quickly. And you don't have to go to Congress at every turn."

The company's team of 36, with 15 nationalities represented, has taken advantage of that milieu. It already owns six stem cell lines made from conventional, noncloned embryos that are approved for U.S. federal funding. Now it is perfecting methods of turning those cells into the kind of pancreatic islet cells that diabetics need, as well as into heart muscle cells that could help heart attack patients. The company is developing new, mouse-free culture systems and sterile production facilities to satisfy regulators such as the U.S. Food and Drug Administration. It hopes to begin clinical tests in humans by 2007.

Despite its research-friendly ethos—and its emphasis on entrepreneurial aspects of stem cell science—Singapore doesn't want to be known as the world's "Wild West" of stem cell research. A panel of scientific and humanitarian representatives spent two years devising ethical guidelines, stresses Hwai-Loong Kong, executive director of Singapore's Biomedical Research Council. Even the public was invited to participate, Kong says—an unusual degree of democratic input for the authoritarian island nation. The country's policies represent a "judicious balance," he says, that has earned widespread public support.

Widespread, perhaps, but not universal. After my conversation with Kong, a government official offered me a ride to my next destination. As we approached her parked car, she saw the surprise on my face as I read the bumper sticker on her left rear window: "Embryos—Let Them Live. You Were Once an Embryo Too!"

"I guess this is not completely settled," I said. "No," she replied, choosing not to elaborate.

That bumper sticker made me feel strangely at home. I am an American, after all. And no country has struggled more with the moral implications of embryonic stem cell research than the U.S., with its high church attendance rates and pockets of skepticism for many things scientific. That struggle promises to grow in the months and years ahead. Many in Congress want to ban the cloning of human embryos, even in those states where it is currently legal and being pursued with private funding. Some states have already passed legislation banning various kinds of embryo research. And federally backed scientists are sure to become increasingly frustrated as the handful of cell colonies they're allowed to work with becomes an ever smaller fraction of what's available.

Yet one thing I've noticed while talking to stem cell experts around the world: Whenever I ask who is the best in the field, the answers are inevitably weighted with the names of Americans. The work of U.S. researchers still fills the pages of the best scientific journals. And while federal policy continues to frustrate them, they are finding some support. Following the lead of California, which has committed 300 million dollars a year for embryonic stem cell research for the next decade, several states are pushing initiatives to fund research, bypassing the federal restrictions in hopes of generating well-paying jobs to boost their economies. Moves like those prompt some observers to predict that when all is said and done, it will be an American team that wins the race to create the first FDA-approved embryonic stem cell therapy.

Tom Okarma certainly believes so, and he intends to be that winner. Okarma is president of Geron, the company in Menlo Park, California, that has been at the center of the embryonic stem cell revolution from the beginning. Geron financed James Thomson's discovery of the cells in Wisconsin and has since developed more than a dozen new colonies. It holds key patents on stem cell processes and products. And now it's laying the groundwork for what the company hopes will be the first controlled clinical trials of treatments derived from embryonic stem cells. Moreover, while others look to stem cells from cloned embryos or newer colonies that haven't come into contact with mouse cells, Okarma is looking no further than the very first colonies of human embryonic stem cells ever grown: the ones Thomson nurtured back in 1998. That may seem surprising, he acknowledges, but after all these years, he knows those cells inside out.

"We've shown they're free of human, pig, cow, and mouse viruses, so they're qualified for use in humans," Okarma says at the company's headquarters. Most important, Geron has perfected a system for growing uniform batches of daughter cells from a master batch that resides, like a precious gem, in a locked freezer. The ability to produce a consistent product, batch after batch, just as drug companies do with their pills is what the FDA wants—and it will be the key to success in the emerging marketplace of stem cell therapies, Okarma says. "Why do you think San Francisco sourdough bread is so successful?" he asks. "They've got a reliable sourdough culture, and they stick with it."

Geron scientists can now make eight different cell types from their embryonic lines, Okarma says, including nerve cells, heart cells, pancreatic islet cells, liver cells, and the kind of brain cells that are lost in Parkinson's disease. But what Geron wants most at this point is to develop a treatment for spinal cord injuries.

Okarma clicks on a laptop and shows me a movie of white rats in a cage. "Pay attention to the tail and the two hind legs," he says. Two months before, the rats were subjected to spinal cord procedures that left their rear legs unable to support their weight and their tails dragging along the floor. "That's a permanent injury," he says. He flips to a different movie: white rats again, also two months after injury. But these rats received injections of a specialized nervous system cell grown from human embryonic stem cells. They have only the slightest shuffle in their gait. They hold their tails high. One even stands upright on its rear legs for a few moments.

"It's not perfect," Okarma says. "It's not like we've made a brand new spinal cord." But tests show the nerves are regrowing, he says. He hopes to get FDA permission to start testing the cells in people with spinal cord injuries in 2006.

Those experiments will surely be followed by many others around the world, as teams in China, the U.K., Singapore, and other nations gain greater control over the remarkable energy of stem cells. With any luck the political and ethical issues may even settle down. Many suspect that with a little more looking, new kinds of stem cells may be found in adults that are as versatile as those in embryos.

At least two candidates have already emerged. Catherine Verfaillie, a blood disease specialist at the University of Minnesota, has discovered a strange new kind of bone marrow cell that seems able to do many, and perhaps even all, the same things human embryonic stem cells can do. Researchers at Tufts University announced in February that they had found similar cells. While some scientists have expressed doubts that either kind of cell will prove as useful as embryonic ones, the discoveries have given birth to new hopes that scientists may yet find the perfect adult stem cell hiding in plain sight.

Maybe Cedric Seldon himself will discover them. The stem cells he got in his cord blood transplant did the trick, it turns out. They took root in his marrow faster than in anyone his doctors have seen. "Everyone's saying, 'Oh my God, you're doing so well,' " his mother says.

That makes Cedric part of the world's first generation of regenerated people, a seamless blend of old and new—and, oddly enough, of male and female. His stem cells, remember, came from a girl, and they've been diligently churning out blood cells with two X chromosomes ever since. It's a detail that will not affect his sexual development, which is under the control of his hormones, not his blood. But it's a quirk that could save him, his mother jokes, if he ever commits a crime and leaves a bit of blood behind. The DNA results would be unambiguous, she notes correctly. "They'll be looking for a girl."

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Harnessing benefits of stem cells for heart regeneration

Asu–mayo clinic collaboration leads to $2.7m nih grant for heart attack recovery research.

Michelle Jang, a biomedical engineering graduate student in the Ira A. Fulton Schools of Engineering at Arizona State University, works on using stem cell technology within conductive hydrogel solution. She is part of Mehdi Nikkhah’s lab team currently studying engineered heart tissues, or EHTs, to improve cell maturation and electrical properties. Photo by Allison Lyne/ASU

Mehdi Nikkhah , an associate professor of biomedical engineering in the  Ira A. Fulton Schools of Engineering  at Arizona State University, and his collaborators at Mayo Clinic in Arizona have been awarded a $2.7 million grant by the National Institutes of Health to research how stem cell engineering and tissue regeneration can aid in heart attack recovery.

The research will be conducted in collaboration with  Wuqiang Zhu , a cardiovascular researcher and professor of biomedical engineering at  Mayo Clinic .

Nikkhah and Zhu are exploring stem cell transplantation to repair and possibly regenerate damaged myocardium, or heart tissue. Their work is focused on the development of a new class of engineered heart tissues with the use of human-induced pluripotent stem cells, or hiPSCs, and has resulted in two published papers in ACS Biomaterials.

Understanding heart attacks

A  heart attack , medically termed as a myocardial infarction, occurs when a coronary artery that sends blood and oxygen to the heart becomes obstructed. This blockage is often the result of an accumulation of fatty cholesterol-containing deposits, known as plaques, within the heart’s arteries.

When these plaques rupture, a cascade of events is initiated, leading to the formation of a blood clot. These blood clots can obstruct the artery, impeding blood flow to the heart muscle, thus triggering a heart attack.

“When someone has a heart attack, a portion of muscle tissue on the left ventricle, which pumps the blood throughout the whole body, is damaged,” Nikkhah says. “Over time, the other parts of the heart have to take on more workload, consequently leading to catastrophic heart failure.”

A team of biomedical engineers in the  School of Biological and Health Systems Engineering , part of the Fulton Schools, and medical researchers at Mayo Clinic in Arizona are taking a novel step forward in using stem cell technology and regenerative medicine to aid in heart attack recovery.

Nikkhah is developing engineered heart tissues, or EHTs, with electrical properties to simulate the contraction function typically found within the native heart’s tissue.

He is integrating the EHTs with gold nanorods to enhance electrical conductivity among stem cells. Gold is a suitable material because it is conductive and nontoxic to human cells, making the nanorods safe for medical research and translational studies.

In the lab, Nikkhah’s team mixes the gold nanorods with a biocompatible hydrogel to form a tissue construct — a patch of stem cells — to rejuvenate damaged cardiac muscle tissue, offering a promising outcome for heart regeneration. 

“After we generate the patch, we get the engineered hiPSCs from Dr. Zhu’s lab at Mayo Clinic,” Nikkhah says. “They seed the cells on the patch and look at their biological characterization, including cell proliferation, cell viability and gene expression analysis, to see how the cells respond to the conductive hydrogel.

“We have successfully used hiPSC-derived cardiomyocytes and cardiac fibroblasts to create beating heart tissues.”

The successful integration and proliferation of these cells can lead to the formation of new, healthy heart tissue, potentially reversing the damage caused by the heart attack and enhancing the recovery process.

Reprogrammed human stem cells have nearly limitless potential because they can be differentiated into various cell types. That means hiPSCs can also be used to construct capillaries and blood vessels, which are essential for restoring adequate blood flow and oxygen supply to the damaged areas of the heart.

​​This process involves the differentiation of hiPSCs into  endothelial cells , which form the lining of blood vessels, thereby facilitating the reconstruction of the heart’s vascular network.

Michelle Jang, a graduate student in Nikkhah’s lab, is currently studying EHTs to improve cell maturation and observe its electrical properties.

“My engagement in this project showed a deep interest in how biomedical engineering technology and biology intersect to create new therapeutic possibilities in the field of regenerative medicine,” Jang says. “I’m excited to see how my current research will further evolve and potentially contribute valuable insights to biomedical research.”

Using these techniques, Nikkhah and Zhu can observe the capacity of programmed cells to regenerate damaged heart tissue. With continued advancement in regenerative medicine, there is potential for significant positive impact on outcomes for patients suffering from heart attacks.

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Collection  13 June 2023

Innovations in Stem Cell Biology 2023

Stem cell models of development, regeneration, and disease are quickly advancing. New technologies and concepts are continuously combined with existing knowledge to create more realistic systems to improve our understanding of these intricate processes.

In this collection, we highlight papers published in 2022-2023 across Nature Portfolio journals on topics including embryonic development and stem cells, reproductive biology, synthetic tissues and embryo models, clinical and translational research and tissue stem cells.

Please review the editorial policies and peer review processes for each participating journal by visiting the links provided in the "Participating Journals" tab.

Robert Stephenson

Nature, Locum Senior Editor

Stylianos Lefkopoulos

Nature Cell Biology, Associate Editor

Madhura Mukhopadhyay

Nature Methods, Senior Editor

Tiago Faial

Nature Genetics, Chief Editor

Elisa Floriddia

Nature Neuroscicence, Senior Editor

Elvira Forte

Nature Cardiovascular Research, Associate Editor

Jerome Staal

Nature Medicine, Senior Editor

Evan Bardot

Nature Communications, Associate Editor

Aline Luckgen

Nature Communications, Senior Editor

Manuel Breuer

Communications Biology, Deputy Editor

Katherine Barnes

Communications Medicine, Senior Editor

• Collection content
• Participating journals

Embryoids and Organoids

Embryo model completes gastrulation to neurulation and organogenesis

Synthetic mouse embryos assembled from embryonic stem cells, trophoblast stem cells and induced extraembryonic endoderm stem cells closely recapitulate the development of wild-type and mutant natural mouse embryos up to embryonic day 8.5.

• Gianluca Amadei
• Charlotte E. Handford
• Magdalena Zernicka-Goetz

Stem cell-derived synthetic embryos self-assemble by exploiting cadherin codes and cortical tension

Bao et al. report that a cadherin code regulates the assembly and sorting of the first three cell lineages during mammalian development and can be manipulated to enhance the efficiency of synthetic embryogenesis.

• Jake Cornwall-Scoones

Enhanced cortical neural stem cell identity through short SMAD and WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells

Rosebrock, Arora et al. report a method to overcome limited cortical cellular diversity in human organoids, thus mirroring fundamental features of cortical development and offering a basis for organoid-based disease modelling.

• Daniel Rosebrock
• Sneha Arora
• Yechiel Elkabetz

Geometric engineering of organoid culture for enhanced organogenesis in a dish

A scalable platform with geometrical reconfiguration of culture systems for long-term growth and maturation of organoids.

• Sunghee Estelle Park
• Dan Dongeun Huh

De novo construction of T cell compartment in humanized mice engrafted with iPSC-derived thymus organoids

Engraftment of human thymic organoids supports de novo development of a functional human T cell compartment in a humanized mouse model.

• Ann Zeleniak
• Connor Wiegand

Lineage recording in human cerebral organoids

A dual-channel recording system for high-resolution lineage tracing.

• Ashley Maynard
• Barbara Treutlein

Automated high-speed 3D imaging of organoid cultures with multi-scale phenotypic quantification

A method for high-content 3D imaging of organoids.

• Anne Beghin
• Gianluca Grenci
• Virgile Viasnoff

Enhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids

Proximal nephron in pluripotent stem cell derived kidney organoids are immature with limited support for functional solute channels. Vanslambrouck et al report improved metanephric specification, generating enhanced kidney organoids with superior proximal tubules, spatially arranged nephrons, and applications for disease research, and drug screening.

• Jessica M. Vanslambrouck
• Sean B. Wilson
• Melissa H. Little

Human multilineage pro-epicardium/foregut organoids support the development of an epicardium/myocardium organoid

Stem cell models of organogenesis are a valuable tool for the study of human development, but often lack the context of tissue-tissue interaction. Here they generate human multi-lineage organoids comprising pro-epicardium, septum transversum, and liver bud, which they co-culture with heart organoids to generate a physiologically relevant model of organogenesis.

• Mariana A. Branco
• Tiago P. Dias
• Maria Margarida Diogo

Progenitors and Progeny

Progress and challenges in stem cell biology

Since stem cells were first discovered, researchers have identified distinct stem cell populations in different organs and with various functions, converging on the unique abilities of self-renewal and differentiation toward diverse cell types. These abilities make stem cells an incredibly promising tool in therapeutics and have turned stem cell biology into a fast-evolving field. Here, stem cell biologists express their view on the most striking advances and current challenges in their field.

• Effie Apostolou

Molecular versatility during pluripotency progression

During development the embryo must balance lineage specification against the preservation of plasticity using a limited molecular toolkit. In this Perspective, the authors propose Molecular Versatility as a paradigm for grouping molecular mechanisms that are repurposed through development to exert distinct functions.

• Giacomo Furlan
• Aurélia Huyghe
• Fabrice Lavial

A 4D single-cell protein atlas of transcription factors delineates spatiotemporal patterning during embryogenesis

A protein expression atlas of transcription factors charted onto cell lineage maps of C aenorhabditis elegans development that uncovers mechanisms of spatiotemporal cell fate patterning and regulators of embryogenesis.

• Zhiguang Zhao

Systematic identification of cell-fate regulatory programs using a single-cell atlas of mouse development

Single-cell RNA-sequencing of seven mouse developmental stages identifies lineage-specific and shared regulatory programs controlling cell-fate decisions. Cross-species analysis associates differentiation potency with ribosomal protein gene expression.

• Lijiang Fei

Bipotent transitional liver progenitor cells contribute to liver regeneration

Transitional liver progenitor cells (TLPCs), which derive from biliary epithelial cells (BECs), differentiate into hepatocytes after serious liver damage. Notch and WNT/β-catenin signaling regulate BEC-to-TLPC and TLPC-to-hepatocyte conversions, respectively.

MLL3/MLL4 methyltransferase activities control early embryonic development and embryonic stem cell differentiation in a lineage-selective manner

Disruption of MLL3/4 enzymatic activities prevents gastrulation and leads to early embryonic lethality in mice. This is largely due to defects in extraembryonic lineages, which compromise developmental progression.

Clonal relations in the mouse brain revealed by single-cell and spatial transcriptomics

Ratz et al. present an easy-to-use method to barcode progenitor cells, enabling profiling of cell phenotypes and clonal relations using single-cell and spatial transcriptomics, providing an integrated approach for understanding brain architecture.

• Michael Ratz
• Leonie von Berlin
• Jonas Frisén

Tmem88 confines ectodermal Wnt2bb signaling in pharyngeal arch artery progenitors for balancing cell cycle progression and cell fate decision

Using zebrafish as a model, Zhang et al. show that Tmem88a/b expression is required to balance proliferation and differentiation of pharyngeal arch artery progenitors into angioblasts by confining ectodermal Wnt2bb signaling.

• Mingming Zhang

Murine fetal bone marrow does not support functional hematopoietic stem and progenitor cells until birth

Relatively little is known about the first hematopoietic stem and progenitor cells to arrive in the fetal bone marrow. Here they characterize the frequency, function, and molecular identity of fetal BM HSPCs and their bone marrow niche, and show that most BM HSPCs have little hematopoietic function until birth.

• Trent D. Hall
• Hyunjin Kim
• Shannon McKinney-Freeman

In vivo clonal tracking reveals evidence of haemangioblast and haematomesoblast contribution to yolk sac haematopoiesis

The lineage relationship between blood and endothelial cells has been difficult to examine due to the multiphasic timing of hematopoiesis in the embryo. Here the authors use using in vivo barcoding technology to assess cell ancestry and show that blood and endothelial cells emerge through common (haemangioblast) or separate (mesenchymoangioblasts and haematomesoblasts) progenitors in the yolk sac.

• T. S. Weber

Stem cell homeostasis regulated by hierarchy and neutral competition

A mathematical model of stem cell homeostasis is presented that comprehensively satisfies hierarchy and neutral competition is presented. The model predicts spontaneous generation of clonal bursts, which is consistent with primate hematopoietic data.

• Asahi Nakamuta
• Kana Yoshido
• Honda Naoki

Mechanical compression creates a quiescent muscle stem cell niche

Mechanical compression drives activated muscle stem cells (MuSCs) into a quiescent stem cell state providing insight into MuSC activity during injury-regeneration cycles.

• Jiaxiang Tao
• Mohammad Ikbal Choudhury
• Chen-Ming Fan

Disease Models and Therapies

Biomechanical, biophysical and biochemical modulators of cytoskeletal remodelling and emergent stem cell lineage commitment

This review highlights the biomechanical, biophysical, and biochemical modulators of cytoskeletal remodeling during tissue neogenesis in early development and postnatal healing for targeted tissue regeneration and regenerative medicine applications.

• Vina D. L. Putra
• Kristopher A. Kilian
• Melissa L. Knothe Tate

Policy for rare diseases

Professor Bobby Gaspar is a distinguished physician-scientist who is a thought leader in translating basic research from bench-to-bedside and strategic work that facilitated bringing life-saving therapies to patients with rare diseases. He has over 30 years of experience in pediatric medicine working in the NHS and the biotechnology sector, and is the founding member of Orchard Therapeutics, where he serves as Chief Executive Officer. In this Q&A, Professor Gaspar provides insight into the regulatory approval and policy considerations for bringing novel therapies for rare diseases from discovery through to clinical application.

Hijacking of transcriptional condensates by endogenous retroviruses

TRIM28 depletion in embryonic stem cells disconnects transcriptional condensates from super-enhancers, which is rescued by knockdown of endogenous retroviruses.

• Vahid Asimi
• Abhishek Sampath Kumar
• Denes Hnisz

CRISPRi screens in human iPSC-derived astrocytes elucidate regulators of distinct inflammatory reactive states

Leng et al. establish CRISPRi screens in astrocytes to dissect pathways controlling inflammatory reactivity. They uncover two distinct inflammatory reactive signatures that are inversely regulated by STAT3 and validate that these exist in human disease.

• Indigo V. L. Rose
• Martin Kampmann

A CRISPRi/a platform in human iPSC-derived microglia uncovers regulators of disease states

Dräger et al. establish a rapid, scalable platform for iPSC-derived microglia. CRISPRi/a screens uncover roles of disease-associated genes in phagocytosis, and regulators of disease-relevant microglial states that can be targeted pharmacologically.

• Nina M. Dräger
• Sydney M. Sattler

Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial

The phase 3 GENESIS trial reports the superiority of the novel CXCR4 inhibitor motixafortide with G-CSF in mobilizing hematopoietic progenitor cells for autologous stem cell transplantation in multiple myeloma.

• Zachary D. Crees
• Michael P. Rettig
• John F. DiPersio

Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study

Phase 1 trial results reveal that intrathecal transplantation of human fetal neural precursor cells in patients with progressive multiple sclerosis is feasible, safe and tolerable.

• Angela Genchi
• Elena Brambilla
• Gianvito Martino

Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial

A phase 1/2a study shows that human neural progenitor cells modified to release the growth factor GDNF are safely transplanted into the spinal cord of patients with ALS, with cell survival and GDNF production for over 3 years.

• Robert H. Baloh
• J. Patrick Johnson
• Clive N. Svendsen

Hydrogel oxygen reservoirs increase functional integration of neural stem cell grafts by meeting metabolic demands

Injectable biomimetic hydrogels hold significant promise for tissue engineering applications. Here, the authors present a hybrid myoglobin:peptide hydrogel to overcome a critical oxygen shortage following neural stem cell transplantation, thus increasing cell survival and integration.

• E. R. Zoneff
• D. R. Nisbet

Bead-jet printing enabled sparse mesenchymal stem cell patterning augments skeletal muscle and hair follicle regeneration

Current mesenchymal stem cell (MSC) transplantation practices are limited by the loss or reduced performance of MSCs. Here the authors develop a bead-jet printer for intraoperative formulation and printing of MSCs-laden Matrigel beads to improve skeletal muscle and hair follicle regeneration.

• Yuanxiong Cao

Msx1 + stem cells recruited by bioactive tissue engineering graft for bone regeneration

Critical-sized bone defects still present clinical challenges. Here the authors show that transplantation of neurotrophic supplement-incorporated hydrogel grafts promote full-thickness regeneration of the calvarium and perform scRNA-seq to reveal contributing stem/progenitor cells, notably a resident Msx1+ skeletal stem cell population.

• Xianzhu Zhang
• Hongwei Ouyang

An instantly fixable and self-adaptive scaffold for skull regeneration by autologous stem cell recruitment and angiogenesis

Limited stem cells and mismatched interface fusion have plagued biomaterial-mediated cranial reconstruction. Here, the authors engineer an instantly fixable and self-adaptive scaffold to promote calcium chelation and interface integration, regulate macrophage M2 polarization, and recruit endogenous stem cells.

• Gonggong Lu
• Xingdong Zhang

Infiltrating natural killer cells bind, lyse and increase chemotherapy efficacy in glioblastoma stem-like tumorospheres

“Super-charged” NK cells kill patient-derived glioblastoma stem-like cells (GSLCs) in 2D and 3D tumor models, secrete IFN-γ and upregulate the surface expression of CD54 and MHC class I in GSLCs.

• Barbara Breznik
• Meng-Wei Ko
• Anahid Jewett

PAM-flexible Cas9-mediated base editing of a hemophilia B mutation in induced pluripotent stem cells

Hiramoto et al. develop a base-editing approach using SpCas9-NG, an engineered Cas9 with broad PAM flexibility, to correct a causative mutation in hemophilia B. Their approach is used to repair the point mutation in patient-derived iPSCs and restore coagulation factor IX expression in HEK293 cells and knock-in mice.

• Takafumi Hiramoto
• Yuji Kashiwakura
• Tsukasa Ohmori

Intraglandular mesenchymal stem cell treatment induces changes in the salivary proteome of irradiated patients

Lynggaard et al. profile the salivary proteome and metaproteome in patients with head and neck cancer who have received radiation therapy and an intraglandular mesenchymal stem cell (MSC) treatment for radiation-induced xerostomia and in healthy controls. MSC therapy impacts the composition of the salivary proteome in the longer-term.

• Charlotte Duch Lynggaard
• Rosa Jersie-Christensen
• Christian von Buchwald

Development and Reproduction

Generation of functional oocytes from male mice in vitro

Mouse induced pluripotent stem cells derived from differentiated fibroblasts could be converted from male (XY) to female (XX), resulting in cells that could form oocytes and give rise to offspring after fertilization.

• Kenta Murakami
• Nobuhiko Hamazaki
• Katsuhiko Hayashi

Metabolic regulation of species-specific developmental rates

An in vitro system that recapitulates temporal characteristics of embryonic development demonstrates that the different rates of mouse and human embryonic development stem from differences in metabolic rates and—further downstream—the global rate of protein synthesis.

• Margarete Diaz-Cuadros
• Teemu P. Miettinen
• Olivier Pourquié

Polycomb repressive complex 2 shields naïve human pluripotent cells from trophectoderm differentiation

Two side-by-side papers report that H3K27me3 deposited by polycomb repressive complex 2 represents an epigenetic barrier that restricts naïve human pluripotent cell differentiation into alternative lineages including trophoblasts.

• Banushree Kumar
• Carmen Navarro
• Simon J. Elsässer

Integrated multi-omics reveal polycomb repressive complex 2 restricts human trophoblast induction

Two side-by-side papers report that H3K27me3 deposited by polycomb repressive complex 2 represents an epigenetic barrier that restricts naive human pluripotent cell differentiation into alternative lineages including trophoblasts.

• Dick W. Zijlmans
• Irene Talon
• Vincent Pasque

A single-cell transcriptome atlas profiles early organogenesis in human embryos

Xu et al. provide a single-cell transcriptomic atlas of 4–6 week human embryos, thereby profiling early human organogenesis.

• Tengjiao Zhang
• Weiyang Shi

Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells

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Human-gained heart enhancers are associated with species-specific cardiac attributes

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New stem cell research takes aim at origins of human cancers

by David McFadden, University of Ottawa

How do cells become cancerous, multiply uncontrollably, and form into tumors? And what role do aberrant embryonic stem cells play? These are big questions explored by medical researchers since the embryonic theory of cancer was first proposed in the 19th century.

Now, in an exciting new study adding to the global pool of knowledge about the roots of human cancers, researchers are establishing a clear link between different types of cancers and their embryonic origins. They also identify new concepts that can be considered in future drug discovery projects and used in standard chemotherapeutics in the clinic.

Published in Cell Chemical Biology , the rigorous study is a collaborative effort by researchers at the uOttawa Faculty of Medicine, McMaster University, and the University of Calgary. Dr. Yannick Benoit is the paper's co-first author along with Dr. Luca Orlando, a postdoctoral researcher in the lab of Dr. Mick Bhatia at McMaster.

Dr. Benoit says that because cancer typically uses blueprints borrowed from embryonic stem cells to promote its propagation in the body, the team first sought to identify drugs that can force human embryonic stems cells to acquire adult tissue specification.

What they observed was highly compelling. They saw that drugs stimulating the formation of the embryonic nervous system were the most effective against brain tumors. Molecules promoting the acquisition of primitive gut features were best at blocking the formation of colon tumors. And drugs pushing embryonic cells toward becoming fetal blood cells were the most effective at killing leukemia.

"Ultimately, we observed that tumors in tissues with the same embryonic ancestry share similar molecular networks that can be targeted to eliminate cancer more effectively," says Dr. Benoit, a principal investigator and assistant professor in the Faculty's Cellular and Molecular Medicine (CMM) department.

It's taken more than a decade for the study to be completed and published. The research began in 2012, and Dr. Benoit worked on portions of the project at McMaster before being recruited to uOttawa in 2017.

This is deeply ambitious research. Essentially, the team was searching for drugs that trigger the specialization of embryonic stem cells toward specific paths of human development. Along the way, they uncovered molecules more effective at re-educating cancer cells based on a path once followed by the affected organ during its fetal life.

"While this concept has been previously proposed over the ages based on observing dissected tumor tissues and inferred through modern computational analyses, our study is the first to provide an experimental demonstration of its applicability in cancer drug discovery," says Dr. Benoit, who last year was recognized by the Gairdner Foundation for his exceptional research achievements and his future potential.

"Our discovery re-emphasizes that cancer is not a single disease, but hundreds of different ones regrouped under the same name. At the end of our journey, we will not find 'the cure' for cancer. Instead, it will be distinct therapeutic avenues with variable chances of success, depending on the type of cancer afflicting a specific patient," he says.

His lab at uOttawa—which aims to create novel anticancer agents that can target epigenetic features of colorectal cancer stem cells—developed the capacity to measure the effect of certain drugs on cancerous stems cells within colon tumor samples. The McMaster and University of Calgary groups were oriented on leukemia and brain tumors .

Together, the team was able to generalize their findings to 30 tumor types and their healthy tissue counterparts with the aid of data sets generated by researchers across the globe and available to the scientific community.

What are the next steps for Dr. Benoit's uOttawa lab as the research team explores questions suggested by this study?

"My lab keeps running searches for candidate drugs to destroy cancer stem cell populations in colon tumors," he says. "Most of our projects start with testing on human embryonic stem cells to see if our compounds of interest alter molecular signatures of early human development."

Journal information: Cell Chemical Biology

Provided by University of Ottawa

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• Published: 06 July 2011

Public perception of stem cell and genomics research

• M William Lensch 1 , 2 , 3  

Genome Medicine volume  3 , Article number:  44 ( 2011 ) Cite this article

7191 Accesses

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The importance of stem cells and genomics for translational research

The confluence of human stem cell and genome research is laden with opportunity. Information gleaned from the Human Genome Project (HGP) has already done much to expand our understanding of human biology and disease (reviewed in [ 1 ]). The same can be said of human pluripotent stem cell (hPSC) research involving human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs). For translational stem cell research, especially where it involves reprogramming of mature cells to make iPSCs and their subsequent directed differentiation to other clinically useful cells and tissues, obtaining a deeper understanding of the role of genome-wide transcriptional and epigenetic alterations will be invaluable. Taking the stem cells and genomics relationship to the next level seems like a good idea.

The availability of hPSCs has accelerated research into the underpinnings of development and genetic disease. Such cells provide abundant starting material for a range of in vitro studies, for example: (i) tissues representing hard-to-access anatomical locations; (ii) a wide variety of genetic backgrounds; (iii) disease models, using iPSCs derived from patients for whom the investigator has access to a detailed clinical history; and (iv) the opportunity to monitor tissue genesis at its earliest stages in health and disease alike (reviewed in [ 2 ]). The current frequency of papers describing novel hPSC-based model systems of human diseases reminds me of the heyday of gene mapping/identification studies in the late 1980s and early 1990s. Back then, it was commonplace to pick up the latest issue of nearly any leading journal and find papers describing disease-causing genes. It felt like a human genetics renaissance.

Today, hPSCs are facilitating new types of hypothesis-driven research in human genetics, including studies of complex, multifactorial conditions. When combined with powerful and ever-cheaper DNA sequencing technology [ 3 ] nothing short of a second renaissance in human genetics research becomes possible. As but one example, iPSCs can be used to generate banks of representative genotypes in certain diseases. The scalability of cultured iPSCs, potential for genetic modification and capacity to differentiate into disease-affected tissues permits extensive studies of genotype-phenotype relationships, the identification of disease-modifying loci and more (reviewed in [ 2 ]).

The public perception of translational stem cell and genomics research

The concert of stem cell and genomics research has great potential; however, it risks amplifying the sour notes of each when it comes to public need, expectation and vulnerability. The emergence of fraudulent 'stem cell clinics' worldwide [ 4 ] led the International Society for Stem Cell Research (ISSCR) to make recommendations regarding the conduct of translational stem cell research [ 5 ]. The potential for harm from unproven cellular therapies further pushed the ISSCR to establish a website providing advice to consumers [ 6 ]. Using this website, individuals may go so far as to request a review of information provided by a 'clinic' offering stem-cell-based treatments.

On the side of genomics, the US Food and Drug Administration has become quite interested in direct-to-consumer marketing of genetic tests [ 7 ]. A recent commentary by J Craig Venter marking the 10th anniversary of the human genome sequence warned of low standards in the translation of personal genomic information to consumers, including potentially 'deceptive marketing' [ 8 ]. It is a story as old as it is unfortunate, in which opportunistic individuals and companies may manipulate hype and hope for financial gain.

Though science is a fascinating endeavor for those of us in the laboratory, we should remember that public support of biomedical research typically relates to unmet clinical need. Investments in the HGP and hPSC research alike have been sold, in part, by articulating their potential to improve human health. Many benefits have already come to pass from this research and more are in store. Unfortunately, despite the best of efforts within laboratories and clinics, a great many people continue to suffer to the point of desperation. Societal expectations for the fruits of stem cell and personal genomics research are high but the general understanding of each, particularly their limitations, is low. This gap in public understanding is a particular concern, especially when it comes to the evaluation of personal medical risk or the drafting of new legislation to regulate science.

Public engagement in translational research

Potentially far-reaching projects, such as those of the ISSCR, are important for improving public understanding of stem cell research. Individual scientists willing and able to personally engage with the public and with policy makers also have a part to play [ 9 ]. Ultimately, people will make their own decisions but doing so from an informed position is the best possible situation. I urge scientists to be engaged. There is too much at stake to do otherwise.

That said, education alone is not the answer, especially when tensions emerge between scientists and the public, such as in the ideological debate around hESC research, or when an individual is motivated by a very personal desire to improve the life of a loved one. In a recent report from the American Academy of Arts and Sciences, entitled Do Scientists Understand the Public [ 10 ], researchers are warned against adopting a 'deficit model'. Such a view holds that 'disconnects' between scientists and lay people stem from public ignorance and that simply educating people will fix things. I am a big proponent of community education in the sciences but it is important to be open-minded when engaging people.

I think that we best serve the public by working to understand what people believe and their reasons for it before presenting our position. This is one difference between being an active participant and an authoritarian. Motivations are often personal and engagement is most effective when it is considerate of individual points of view, even if they are scientifically flawed. People sometimes do things despite having solid information to the contrary, especially if the only other option is to do nothing. This is part of the complexity of human existence in general and interactions with a medically needy but autonomously acting public in particular [ 11 ].

The American Academy of Arts and Sciences report also stresses the importance of anticipating problems before they arise [ 10 ]. Researchers need to be ahead of the curve in the interplay between science and society, including the shaping of policy. Failing to engage early puts scientists into a reactionary position from which it is difficult to promote change. Public involvement in translational stem cell and genomics research will only become more important, such as in studies where larger and more genetically diverse populations are beneficial, not to mention in future clinical trials.

My bottom line is this: combining stem cell and genome technologies is a terrific idea. I foresee a deeper understanding of human development and disease as a result of this union and, thus, a shorter path to improved therapies. An important corollary is that people are waiting for improvements in medical care and they are understandably impatient. This presents its own opportunities, not only to put new information on the table, but to partner with the public and policy makers in a way that ensures support. When such relationships also promote greater consumer protection against sham therapies, I fail to see a downside to engagement.

Abbreviations

human embryonic stem cell

• Human Genome Project

human pluripotent stem cell

induced pluripotent stem cell

International Society for Stem Cell Research.

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Hyun I, Lindvall O, Ahrlund-Richter L, Cattaneo E, Cavazzana-Calvo M, Cossu G, De Luca M, Fox IJ, Gerstle C, Goldstein RA, Hermerén G, High KA, Kim HO, Lee HP, Levy-Lahad E, Li L, Lo B, Marshak DR, McNab A, Munsie M, Nakauchi H, Rao M, Rooke HM, Valles CS, Srivastava A, Sugarman J, Taylor PL, Veiga A, Wong AL, Zoloth L, Daley GQ: New ISSCR guidelines underscore major principles for responsible translational stem cell research. Cell Stem Cell. 2008, 3: 607-609. 10.1016/j.stem.2008.11.009.

ISSCR: A closer look at stem cell treatments. [ http://www.closerlookatstemcells.org//AM/Template.cfm?Section=Home ]

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Murdoch CE, Scott CT: Stem cell tourism and the power of hope. Am J Bioeth. 2010, 10: 16-23.

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Acknowledgements

The author sincerely thanks Ms Andrea Fiorillo and Ms Anne Cherry, and Drs Asmin Tulpule, Hao Zhu and Katayoun Chamany. Space limitations force an abbreviated bibliography and the author apologizes for omitting relevant citations as a result. MWL is supported by a Howard Hughes Medical Institute Investigator Award to George Q Daley.

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M William Lensch

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Lensch, M.W. Public perception of stem cell and genomics research. Genome Med 3 , 44 (2011). https://doi.org/10.1186/gm260

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Stem Cell Research as Innovation: Expanding the Ethical and Policy Conversation

Rebecca dresser.

Daniel Noyes Kirby Professor of Law and Professor of Ethics in Medicine at Washington University in St. Louis.

In 1998, researchers established the first human embryonic stem cell line. Their scientific triumph triggered an ethics and policy argument that persists today. Bioethicists, religious leaders, government officials, patient advocates, and scientists continue to debate whether this research poses a promise, a threat, or a mixed ethical picture for society.

Scientists are understandably excited about the knowledge that could come from studying human embryonic stem cells. Most of them believe these cells offer a precious opportunity to learn more about why diseases develop and how they might be prevented or attacked. In their quest to gain support for stem cell research, scientists and others have claimed that the research could generate cures and treatment for everything from heart disease to cancer.

Although most people are now familiar with claims about the diverse medical benefits stem cell research might deliver, they are less familiar with the diverse ethical issues relevant to the research. Most of the ethics debate focuses on the morality of destroying human embryos for the benefit of others. This is an important issue, but stem cell research raises other important ethical issues — issues that have received relatively little attention in the public arena. After more than a decade of narrowly focused analysis, it is time to expand the discussion.

The debate over embryonic stem cell research should consider a diversity of ethical and policy issues. Many of the ethical and policy issues that stem cell research presents apply to biomedical research in general, such as questions about appropriate research priorities and allocation of limited resources for research and health care. In this sense, the debate over stem cell research offers an opportunity to examine a variety of ethical and policy issues raised by biomedical innovation.

In this article, I place stem cell research in a broader ethics and policy context by describing three considerations that merit more attention in the debate. These include the following: (1) truth-telling and scientific integrity; (2) priorities in resource allocation for research and health care; and (3) responsibilities in civic discourse about bioethical controversies.

Truth-Telling and Scientific Integrity

New breakthroughs in biomedical science are often hailed as potential cures for the diseases that plague modern society. In many cases, however, the breakthroughs fall short of initial expectations. Innovations such as the artificial heart, fetal tissue transplantation, and gene therapy proved disappointing when they were tested in humans.

A similar result could occur with stem cell research. The excitement over stem cell research is unprecedented, and this creates fertile ground for exaggeration. Researchers, patient advocates, and politicians promise stem cell remedies for nearly every major health problem in the United States. And the promises come from both supporters and opponents of embryonic stem cell research. Supporters stress the advances possible through embryonic stem cells, while opponents emphasize potential therapeutic benefits from adult stem cells and other alternative sources. 1

The predictions on both sides violate the ethical responsibility to be accurate in describing the state of scientific exploration. Although there are a few established therapies that employ adult stem cells, most of the claims about stem cell therapies lack a solid evidentiary foundation. Much of the existing data comes from laboratory and animal studies. The first human trial of an embryonic stem cell intervention did not begin until 2009. 2 It will be many years before researchers can gather the human data necessary to determine whether stem cells will live up to their promise.

Much remains to be learned about the therapeutic abilities of stem cells. The cells’ treatment potential lies in their capacity to develop into different types of specialized human cells. The hope is that they could replace cells damaged through illness or injury. For this to work, however, scientists must understand more about how transplanted cells behave in the human body. They must also develop the power to control how the cells develop. Without this power, the cells could cause cancer or other harm to the recipient.

Because the immune system rejects foreign tissue, immune rejection is another possible barrier to effective therapies. 3 In theory, the problem could be solved by using stem cells created from a cloned embryo made with an individual patient’s somatic cell, but this procedure appears to present significant scientific challenges. 4 Moreover, economic and practical difficulties could impede efforts to devise therapies using stem cells from cloned embryos. 5 More work is also needed to determine whether induced pluripotent cells, the latest potential substitute for embryonic stem cells, could be safe and effective sources of replacement tissue. Novel uses of other kinds of adult stem cells also need further investigation to determine their clinical utility. 6

These and other scientific uncertainties make unqualified or barely qualified claims about therapies and cures from stem cell research ethically suspect. Ordinary people, including patients and their families, may be misled by such claims. They may develop unfounded hope for relief in a matter of months or years, rather than a more realistic understanding. They will be sorely disappointed once they become aware of the “significant technical hurdles… that will only be overcome through years of intensive research.” 7

Inflated promises about stem cell benefits can harm vulnerable people and can harm the research endeavor, as well. When members of the public realize that much work remains before effective therapies can be devised, their support for stem cell studies may diminish. They may become less willing to urge government support for the research, and less willing to contribute to nonprofit organizations supporting stem cell research.

The hype about stem cell research threatens scientific integrity, too. The field was undermined when the world learned of the fraud committed by South Korean researchers who claimed they had created stem cell lines from cloned human embryos. Besides dismay at the research team’s failure to observe basic standards of scientific integrity, there was speculation that editors and peer reviewers at Science , the journal that published the research, were too eager to publish the cloning reports. Some wondered whether scientists’ enthusiasm for the stem cell field led them to be less demanding than they should have been in their scrutiny of the research claims. 8

Other threats to scientific integrity arise when stem cell research becomes the basis for exaggerated claims by interest group lobbyists. Scientific organizations have claimed that limits on government funding for embryonic stem cell research could damage U.S. scientific preeminence. In the funding controversy’s early years, critics predicted a huge “brain drain” as U.S. scientists migrated to other nations offering generous support for the research. 9 Yet few scientists actually left this country to engage in stem cell research. 10 Several states stepped in to offer substantial funding, and nonprofit and private-sector support became available, too. 11 Even before the Obama administration revised the federal funding policy, U.S. researchers had many opportunities to pursue embryonic stem cell research.

Stem cell research has become a hot-button political issue, and this development could tarnish the public’s respect for and trust in science. Traditionally, science has enjoyed bipartisan support in the U.S., and in many respects, it still does. The debate over government funding for embryonic stem cell research does not divide along party lines. At the same time, however, politicians and their supporters have used the stem cell cause to advance partisan objectives. As one observer reported in 2006, “Politicians from both major parties are trying to use such research as a ‘wedge issue’ to woo voters.” 12

During the past decade, stem cell research became enmeshed in partisan politics from the national to the local level. Senator John Kerry made his support for federal funding of embryonic stem cell research a major theme in his 2004 campaign for the presidency. 13 For his part, former president Bush used his opposition to embryo destruction for research as a means to advance his campaign. 14 In the 2008 presidential election, both candidates claimed to support expanded federal funding for embryonic stem cell research, but the issue became politicized when research advocates warned that Senator John McCain’s position might change if he were elected. 15 Stem cells have also taken center stage in some state elections. In my own state of Missouri, where an initiative about stem cell research was on the November 2006 ballot, U.S. Senate and even county council candidates made stem cell research central to their election efforts. 16 The topic was a major issue in the 2006 New York governor’s race as well. 17

Stem cell research has joined abortion as a controversial matter on which politicians are expected to take a stand. It has become impossible to insulate this type of research from political debate. If stem cell research becomes identified with a particular political party or with specific candidates, then its fate could be determined more by politics than by substantive results in the laboratory. 18

There is one positive development in the public discussion about stem cell research. Many stem cell research supporters have begun to convey more realistic messages about the prospects for stem cell therapies. 19 In an ironic twist, one of the cautionary voices is James Wilson, who led the gene transfer trial in which Jesse Gelsinger died. Recounting the problems that came from the hype and haste surrounding clinical trials of gene transfer interventions, Wilson wrote in 2009, “I am concerned that expectations for the timeline and scope of clinical utility of [human embryonic stem cells] have outpaced the field’s actual state of development and threaten to undermine its success.” 20 He called on stem cell researchers and professional organizations, like the International Society for Stem Cell Research, to “steadfastly discourage” the exaggeration characterizing many claims about medical benefits from stem cell research. 21

Like Wilson, more experts and journalists express caution about the potential for stem cell therapies and focus instead on the value of stem cells as basic science tools that could help researchers understand how and why diseases develop. 22 But it is still easy to find examples of hype about stem cell therapies, such as in the publicity surrounding the first human trial of an embryonic stem cell intervention. 23

Like the Human Genome Project, stem cell research is most likely a form of scientific inquiry whose benefits will emerge slowly and incrementally. (Indeed, the Human Genome Project is now criticized as a costly research effort that to date has produced few actual medical benefits. 24 ) Rather than presenting stem cell research as a short-term answer for today’s patients, supporters should portray it as a promising scientific development that might, after many years of investigation, contribute to new medical interventions. 25 Just as physicians should be honest in disclosing a poor prognosis to a patient, scientists and advocacy groups should be honest about the lack of certainty that stem cell research will produce cures and effective therapies.

Social Justice and Allocation of Limited Resources

Stem cell research raises general questions about the appropriate allocation of government and private resources in biomedicine. One set of allocation questions addresses priority setting in biomedical research. The other set of allocation questions concerns the relative priority of research versus health care in funding decisions. These are questions that apply to biomedical research in general, but stem cell research nicely illustrates the relationship between research funding choices and social justice considerations.

Stem cell research is just one form of promising research. The National Institutes of Health (NIH), the largest public funder of biomedical science, supports many kinds of research offering opportunities to advance knowledge. The research portfolios of industry and nonprofit organizations also reveal an array of promising research areas. But neither the public nor the private sector can support every promising research project. Every research funding source has limited resources. As a result, these entities face hard choices about where to invest their limited dollars. How should funding agencies, nonprofit organizations, and private companies decide where to channel their resources?

According to NIH officials, five considerations play a role in the agency’s spending choices: (1) public health needs; (2) scientific merit of specific study proposals; (3) potential for advances in a particular area; (4) distribution across diverse research areas (because it is impossible to predict exactly where advances will occur); and (5) national training and infrastructure needs. The first criterion, public health needs, is determined by the following factors: (1) number of people with a specific disease; (2) number of deaths a specific disease causes; (3) degree of disability a specific disease produces; (4) how much a specific disease shortens the average lifespan; (5) a specific disease’s financial and social costs; and (6) the threat posed to others by contagious disease. According to the NIH, all of these considerations play a role in allocating research resources; none is rated as more important than another. 26

In the private sector, industry tends to allocate funds to research on conditions and products offering the greatest potential for financial reward. Many nonprofit organizations represent a single disease or demographic group and use their limited funds to support research that could benefit their specific constituencies.

The choices these entities make about research funding allocation raise social justice issues. As a publicly funded agency, the NIH has a duty to distribute its resources in a just manner. People disagree about whether private organizations have justice-based obligations, but a growing literature on corporate responsibility contends that even for-profit entities have a duty to consider the public good in their decision making. 27

What qualifies as a just approach to allocation of resources for research? The NIH priority-setting criteria incorporate justice-based considerations, but they are quite general. Moreover, officials have been unwilling to rank the criteria in order of importance. This means that the agency takes no position on the relative importance of, for example, research aimed at conditions that shorten the average lifespan and research aimed at conditions affecting the most people. In reality, critics say, the priority-setting criteria are so loose that congressional politics often determines where NIH dollars are directed. 28

The NIH criteria also leave open a significant social justice question, which is whether the U.S. has obligations to support research primarily aimed at helping people in poor nations. Some would contend that research funded by the U.S. government should address only domestic health concerns, but for many years, NIH has funded some international health research. There has been little public discussion of whether this approach is appropriate, however, and if it is appropriate, what portion of the NIH budget should be devoted to the health problems of people in other countries. 29

Although the proper approach to research priority setting is contested, the NIH criteria offer a framework for evaluating stem cell research. Much stem cell research is aimed at understanding and treating chronic diseases of aging, such as heart disease and neurological diseases. Indeed, some advocates proclaim that stem cell research will pave the way to “regenerative medicine,” in which the tissues and organs that deteriorate with age will be replaced with new ones created from stem cells. According to this group, interventions developed through stem cell research will substantially extend the human life span. 30

Not only are these predictions inconsistent with the duty to acknowledge the uncertainties accompanying early-stage research, they also raise resource allocation questions. Should extending the average U.S. life span be a high priority in research funding decisions? Would it be more defensible to give conditions that cause premature death a higher priority? Should strategies targeting prevention rather than treatment have a higher priority? 31

Another factor is the costs of the treatments that might emerge though stem cell research. Although basic science studies involving stem cells might help researchers develop new drugs and other relatively affordable medical interventions, the stem cell therapies that regenerative medicine enthusiasts describe could be relatively costly. As one group considering justice issues raised by stem cell research observed, “It seems inevitable, and of serious moral concern, that there will be significant economic barriers to access to new therapies utilizing stem cells or other cell-based preparations.” 32 If stem cell research produces expensive treatments, how many people will be able to benefit from the research investment? 33

Even more dramatic social justice questions arise when one considers biomedical research in an international context. Research is concentrated in wealthy nations and much of it focuses on the health problems of people fortunate enough to live in those nations. 34 Stem cell research is a prime example of this phenomenon, since much of the research (although not all of it) targets conditions arising later in life. But does justice require that prosperous nations devote more of their research funds to conditions that cause premature death in poor countries? 35

Questioning the justice of research funding allocation decisions may seem sacrilegious, given how popular biomedical science is in this country. But bioethicist Daniel Callahan presents the following thought experiment:

[C]onsider — as an imaginative exercise — what we would get if there was no progress at all from this point forward, and medicine remained restricted to what is now available. The rich countries would remain rich. Most of their citizens would make it to old age in reasonably good health. There would continue to be incremental gains in mortality and morbidity, the fruits of improved social, economic, and educational conditions, and improvements in the evaluation and use of present therapies. No prosperous country would sink from the lack of medical advances. 36

Another startling take on research priorities comes from neuroscientist Floyd Bloom. In his 2003 presidential address to the American Association for the Advancement of Science, Bloom declared that the quest for improved health care should focus more on health outcomes research than on the genomics research so often portrayed as a vehicle to medical advances. 37 These points provide a basis for considering stem cell research in a broader research context. Although stem cell research might eventually deliver benefits to some patients, benefits could also be achieved by investing resources in other kinds of research.

The social justice inquiry is relevant to many areas of biomedical research, not just stem cell research. Indeed, such an inquiry might support research on some conditions that are the focus on stem cell research, such as juvenile diabetes and spinal cord injury, which affect many young people. Nevertheless, it is important to see stem cell research as simply one of many scientific opportunities that could deliver health benefits. Investments in stem cell research will reduce the funds available for other types of biomedical research. In stem cell research, as in other research areas, the relative value and likely cost of any potential therapeutic benefits should be part of the decision making about research priorities.

A second matter of social justice concerns the relative priority of research needs and health care needs. Is it more important to conduct research aimed at improving care for future patients, or to provide better health care to today’s patients? In the U.S., as Daniel Callahan observes, “[T]he research drive has received an awful lot of money and great attention, but we have done less well with the delivery of health care….” 38 Because millions of people lack health insurance coverage and millions more have inadequate coverage, many patients are unable to benefit from the clinical interventions developed through past research efforts. 39 Is it ethical to devote large sums of money to research while so many people lack access to medical care that could give them longer and better lives?

Supporters contend that stem cell research is needed to aid patients with conditions that cannot be treated with existing therapies. From this perspective, there is a social justice basis for channeling limited resources to stem cell research. But those defending a moral duty to conduct stem cell research should consider another social justice perspective. Expanding access to health care would assist a currently disadvantaged group of people. Most standard health care interventions have been studied and found to be reasonably effective. Many are also relatively affordable. For these reasons, directing limited resources to health care delivery might achieve social justice objectives more efficiently than directing resources to stem cell research. This argument has even more force in the international context. Lack of access to basic health care, clean water, and other public health services produces high death rates in poor countries. 40 In this situation, small amounts of money can make huge contributions to improving and extending human lives.

What justifies our nation’s substantial investment in biomedical innovation, when millions of people here and abroad are denied access to proven medical interventions? 41 Once again, the stem cell controversy opens a window to a larger moral problem. The social justice inquiry raises questions about the priority that stem cell and other basic science studies should have in the competition for limited resources. If government officials and health advocates want to help patients, meaningful help would also come from a system that supplied adequate health care to more people, both across the nation and worldwide.

Responsibilities in Civic Discourse

People have passionate views on stem cell research. Their passion has had two detrimental effects on the public debate. One is the exaggeration about therapeutic benefits I referred to earlier. The other is disrespect for people with opposing positions. Too often, people caught up in the debate portray those with different positions inaccurately and unfairly.

Opponents of embryonic stem cell research use the slippery slope to cast aspersions on the morality of research supporters. According to some opponents, research supporters will accept almost anything to advance science and human health. Thus, for example, those who would allow the creation and destruction of human embryos to advance knowledge will also accept a world in which human beings are “grown for spare body parts.” 42 And any move to allow early embryos to be destroyed in research “will provide the leverage to thrust the research door open for Franken-steinian experimentation on the most vulnerable of our species.” 43

On the other hand, people supporting embryonic stem cell research belittle those assigning a high moral status to early human embryos. Underlying this attitude is disdain for anyone who would let religious and other moral beliefs influence their positions on science policy. Some scientists and advocates recognize that scientific considerations alone cannot determine appropriate state policy on embryonic stem cell research. 44 Others, however, seem to assume that morality has no place in the debate, or alternatively, that no rational individual could assign a high moral status to the early human embryo. As a columnist who supports embryonic stem cell research put it, “Only Bush bitter-enders and the pope are in the perverse position of valuing the life of an ailing human being less than that of a tiny clump of cells no bigger than the period at the end of this sentence.” 45

Misleading terminology also characterizes the stem cell debate. For example, many embryonic stem cell research supporters deny that they endorse human cloning. 46 Implicit in this claim is a narrow definition of human cloning that covers only the creation of a child through cloning. But the initial process of creating the cloned embryo (which research supporters prefer to call somatic cell nuclear transfer) is the same in research cloning and cloning to have children. 47 People who believe that the early human embryo has a high moral status do not differentiate between the two activities. Yet speakers often fail to clarify which definition of cloning they adopt, which leads to confusion in the public debate.

Also misleading is the term “therapeutic cloning,” which suggests to the layperson that this is a procedure with proven clinical benefit, rather than one that remains theoretical at this point. And in yet another form of terminology manipulation, embryonic stem cell research supporters characterize their proposals for liberal federal funding policies as efforts “to promote all ethical forms of stem cell research.” 48 This characterization avoids what is at the heart of the policy controversy, which is the question of whether or not research requiring embryo destruction is ethical. Such language games fail to give due regard to the moral disagreements underlying the policy disputes over stem cell research.

Decisions about U.S. stem cell research — whether to prohibit, regulate, permit, or financially support it — occur in the democratic context. The ongoing debates over stem cell research ought to reflect a better deliberative process than we have seen so far. In their work on deliberative democracy, political scientists Amy Gutmann and Dennis Thompson offer guidance for improving the deliberations over stem cell research. Below I describe their general framework for deliberative democratic policymaking and then apply it to stem cell policy formation.

Gutmann and Thompson describe four deliberative democracy characteristics relevant to stem cell research policy. First, policy arguments and choices must be supported by reasons. The requirement for reason-giving rests on a moral principle that underlies democracy: the principle that citizens should be regarded as agents participating in their society’s decisions. To participate in a democracy, citizens must understand why certain choices are made. Learning the basis for official actions allows people to challenge decisions that rest on false or misleading reasons. The reason-giving requirement also demonstrates respect for all citizens, no matter what their economic or political power happens to be. All are entitled to an explanation for the policies their officials impose. 49

Gutmann and Thompson describe a second feature of deliberative democracy, which is that the reasons underlying a policy must be accessible to all affected by that policy. Accessible reasons are understandable not only to those agreeing with the policy, but also to those opposing it. To fulfill this requirement, decision makers must publicly articulate their reasons for a specific policy choice and those reasons must have an acceptable public content. This means that reasons should rest on facts, rather than false information. Members of the public should also be able to evaluate the beliefs supporting a policy choice: “It would not be acceptable, for example, to appeal only to the authority of revelation, whether divine or secular in nature.” 50 In a deliberative democracy, Thompson and Gutmann maintain, individuals can disagree with a policy and at the same time conclude that the policy has a legitimate basis.

Deliberative democracy’s third characteristic addresses the status of policies over time. Deliberations are aimed at a specific policy decisions, and at some point those decisions must be made. Policies then become binding on citizens. But deliberative democracy requires that policies remain open to revision. If new facts are discovered that undercut the initial policy choice, officials should reassess their original choice. If emerging discoveries or events provoke people to new value judgments affecting their policy views, officials should take these changes into account. People should be free to challenge existing policies, and officials should make revisions when they are justified. As Thompson and Gutmann observe, those disagreeing with a policy choice will be more likely to accept it if they know they can in the future work to alter that choice. 51

Thompson and Gutmann discuss a fourth dimension of deliberative democracy with special relevance to the stem cell research debate. Participants in deliberations should aim for what Thompson and Gutmann call “economy of moral disagreement.” 52 This concept comes from the deliberative directive to respect those with values and positions that differ from our own. The concept “does not ask us to compromise our moral understandings in the interest of agreement, but rather to search for significant points of convergence between our own understandings and those of citizens whose positions, taken in their more comprehensive forms, we must reject.” 53 Deliberative democracy asks parties in disagreement to seek common ground, sometimes forgoing their ideal policies for ones that elicit greater agreement. 54

Policy debates about stem cell research should incorporate these features. Proponents of different policies should offer accessible reasons for their positions. For example, research supporters should go beyond simplistic slogans linking stem cell research with lifesaving cures. They should supply clear and accurate information about potential clinical results, tempering the promises of effective therapies with realistic accounts of what must be achieved before therapies become available. In turn, people promoting alternatives to embryonic stem cell research should supply clear and accurate information about adult stem cells, induced pluripotent cells, and other alternative sources that avoid embryo destruction. They too should speak of therapies as possibilities that remain uncertain and probably many years away. Both groups should emphasize that most stem cell work remains in the laboratory and that no one can say whether or when medical applications will emerge from that work.

Both advocates and opponents of embryonic stem cell research should also do a better job of confronting the moral questions raised by their positions. Those whose views reflect religious beliefs about the moral status of early human embryos should offer reasons for their positions that can be accepted by people who fail to share those beliefs. Those who claim to see the human embryo as an entity owed special respect should explain why embryo destruction is consistent with this moral status position. People worried about risks to women providing eggs to create embryos for stem cell research should explain why the usual human subject protections are inadequate in this situation. And those who think the risks to women are justified should consider how they will respond if women experience harm from the egg production process.

Adversaries in the stem cell debate should aim for an economy of moral disagreement as well, seeking to develop policies that individuals with differing positions could accept. For example, if people on both sides agree that the goal of improved health care justifies government funding for stem cell research, federal officials could decide to pursue that goal in a manner that demonstrates respect for those opposed to embryo destruction. Officials could for a limited time period fund only stem cell research using cells from alternative sources. If suitable alternatives failed to emerge during that time, government support could be redirected to research involving stem cells from destroyed embryos. A similar policy approach could be taken to research cloning, with support initially directed to research aimed at developing patient-matched stem cells through methods that avoid the need for donated eggs.

Policies incorporating the reverse presumptions might also be devised. Such policies would authorize financial support for embryonic stem cell research from IVF and cloned embryos for a limited period, but would cease such support once alternative sources became available. 55 Policies like these would demonstrate respect for those holding different positions on the ethics of creating and destroying embryos for research. And these options are not the only possibilities. A deliberative commitment in policy development could yield a variety of options that accommodate to some degree the different moral positions on stem cell research.

How does the latest development in federal policy look through the lens of deliberative democracy? In the 2009 revision of the federal funding policy for stem cell research, some features of deliberate democracy were evident, but there were deliberative shortcomings as well. In announcing his plans to liberalize the policy, President Obama cautioned against exaggerating the possibility of medical benefits from the research. At the same time, he characterized the research as a step toward the “day when words like ‘terminal’ and ‘incurable’ are potentially retired from our vocabulary.” 56 He recognized the moral opposition of “thoughtful and decent people” to embryonic stem cell research and spoke of avoiding the “perils” the research presents through “proper guidelines and strict oversight.” 57 But he neither defined those perils nor explained how guidelines and oversight would avoid them. Thus, the president gave a nod to the moral dispute and the importance of supplying accessible reasons for the position he endorsed, but the deliberative effort was relatively superficial.

The final NIH Guidelines on Human Stem Cell Research 58 also exhibit deliberative strengths and weaknesses. The guidelines permit federal funding for research on stem cell lines created from embryos donated by couples who have completed their infertility treatment. But the guidelines rule out funding for research using lines created from embryos produced purely for research. In published commentary on the guidelines, NIH officials said there was “broad public support” for funding research using stem cells from donated embryos, but that “a similar consensus has not emerged” on the ethics of creating stem cells through procedures like cloning, in part because they require women to provide eggs at some risk to their health. 59 In this respect, we can see an effort to provide accessible reasons for the decision and, possibly, to economize moral disagreement by allowing only limited expansion of the funding rules.

But another aspect of the guidelines failed to conform to deliberative ideals. In a telephone press briefing on the final guidelines, Acting NIH Director Dr. Raynard Kington said the agency had received thousands of comments opposing government funding of any research using stem cell lines created through embryo destruction. The official commentary on the guidelines neither mentions those comments nor explains why they did not prevail. In the telephone briefing, Dr. Kington said that agency officials deemed the comments “nonresponsive” to their request for comments on the guidelines they had proposed earlier in the year. 60 A robust deliberative approach would have acknowledged the high number of opposing comments and devoted at least a few sentences to explaining why the agency’s position differed from that taken in the comments. 61

Stem cell research could generate knowledge that would allow certain individuals to live longer and better lives. It would be a happy event if in the future stem cell research produced relief for at least some individuals with illnesses or injuries not curable at present. Yet there are no guarantees that this happy future will materialize. Although we may support and admire the scientists devoted to developing a better understanding of human health and disease, we should also be aware that no one can ensure that effective treatments will emerge.

The therapeutic benefits of stem cell research are possible, but uncertain. And many other areas of biomedical science fit this description. Stem cell research is not the only field in which exciting discoveries are occurring and future patients may benefit from investments in these areas, too. This is not a reason to deny support to stem cell research, but it is a reason to consider it in a larger context. Advocates weaken their case when they portray stem cell research as if it were the only promising research around. 62 More government support for stem cell research could help patients in the future, but so could support for research in other biomedical fields.

Participants in the stem cell debate should also recognize deficiencies in the health system denying patients the benefits of past research. Advocacy for stem cell research should include advocacy for a better health system. Without improvements in this system, any therapeutic benefits developed through stem cell research will be unjustly limited to patients fortunate enough to have access to the best health care. 63

Moreover, the stem cell controversy should press us to reexamine existing research and health care priorities. Should officials devote more funds to research aimed at translating laboratory discoveries into actual clinical benefits? 64 Should they channel more funds to studies that could have a significant public health impact? And what level of investment should the U.S. make in programs aimed at developing and delivering affordable care to disadvantaged people in this nation and around the world? These are ethical questions with immense significance, but they are often overlooked amid the excitement over specific research discoveries like those involving stem cell research.

Last, ethical considerations sometimes justify setting limits on scientific innovation. For example, there is nearly universal agreement that people should not be forced to participate in research, even though a coercive research policy could generate extremely valuable knowledge. Some people believe there should also be severe limits on research involving early human embryos, while others disagree. These are not disputes that science can settle. They are instead value conflicts to be expected in a pluralistic society like ours. In struggling with these conflicts, we should maintain respect for those holding differing views, and we should look for policies that are consistent with as many of those views as possible.

Advocates often portray stem cell research as presenting a choice between ending human life and saving human life. 65 But the choices are much more complicated than that. Many ethical considerations are relevant to policy choices about stem cell research, but they often go unmentioned. Instead, the sound bite approach to stem cell research has produced a shrill and divisive policy climate. Fewer sound bites and an expanded ethical conversation could produce more defensible policy decisions about stem cell research.