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• 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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Wojciech Zakrzewski, Maria Szymonowicz & Zbigniew Rybak

Department of Conservative Dentistry and Pedodontics, Krakowska 26, Wrocław, 50-425, Poland

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WZ is the principal author and was responsible for the first draft of the manuscript. WZ and ZR were responsible for the concept of the review. MS, MD, and ZR were responsible for revising the article and for data acquisition. All authors read and approved the final manuscript.

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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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• Differentiation
• Pluripotency
• Induced pluripotent stem cell (iPSC)
• Stem cell derivation
• Growth media
• Tissue banks
• Tissue transplantation

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Stem cells: past, present, and future

Affiliations.

• 1 Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345, Poland. [email protected].
• 2 Department of Conservative Dentistry and Pedodontics, Krakowska 26, Wrocław, 50-425, Poland.
• 3 Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345, Poland.
• PMID: 30808416
• PMCID: PMC6390367
• DOI: 10.1186/s13287-019-1165-5

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.

Keywords: Differentiation; Growth media; Induced pluripotent stem cell (iPSC); Pluripotency; Stem cell derivation; Stem cells; Teratoma formation assay; Tissue banks; Tissue transplantation.

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Oocyte development and formation of…

Oocyte development and formation of stem cells: the blastocoel, which is formed from…

Changes in the potency of…

Changes in the potency of stem cells in human body development. Potency ranges…

Spontaneous differentiation of hESCs causes…

Spontaneous differentiation of hESCs causes the formation of a heterogeneous cell population. There…

Culturing of pluripotent stem cells…

Culturing of pluripotent stem cells in vitro. Three days after fertilization, totipotent cells…

Retroviral-mediated transduction induces pluripotency in…

Retroviral-mediated transduction induces pluripotency in isolated patient somatic cells. Target cells lose their…

Stem cell experiments on animals.…

Stem cell experiments on animals. These experiments are one of the many procedures…

Localization of stem cells in…

Localization of stem cells in dental tissues. Dental pulp stem cells (DPSCs) and…

Use of inner cell mass…

Use of inner cell mass pluripotent stem cells and their stimulation to differentiate…

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100 Stem Cell Research Topics + Examples

Are you looking for stem cell research topics? StudyCorgi has compiled a list of stem cell topics suitable for a research paper, essay, presentation, thesis, and other assignments. Our proposed titles go beyond examining the pros and cons of stem cell research and therapy and provide many fresh insights on this subject. We hope that our list will give you inspiration for developing your own project ideas.

🏆 Best Stem Cell Research Topics

🔎 easy stem cell research paper topics, 🎓 most interesting stem cell research paper topics, 💡 simple stem cell research topics for research paper, ❓ stem cell research questions.

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• How Is Stem Cell Research Similar to Developmental Biology?
• Where Do Adult Somatic Stem Cells Originate?
• Which Type of Stem Cell Gives Rise to Red and White Blood Cells?
• Should Stem Cell Research Be Legal?
• What Would Happen if Human Doesn’t Have Stem Cells?
• What Is Using Stem Cells to Produce Healthy Tissues to Treat Degenerative Diseases Called?
• What Is the Difference Between the Different Kinds of Stem Cells?
• What Part of a Human Bone Contains Stem Cells?

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StudyCorgi. (2022, May 10). 100 Stem Cell Research Topics + Examples. https://studycorgi.com/ideas/stem-cell-essay-topics/

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StudyCorgi . 2022. "100 Stem Cell Research Topics + Examples." May 10, 2022. https://studycorgi.com/ideas/stem-cell-essay-topics/.

These essay examples and topics on Stem Cell were carefully selected by the StudyCorgi editorial team. They meet our highest standards in terms of grammar, punctuation, style, and fact accuracy. Please ensure you properly reference the materials if you’re using them to write your assignment.

This essay topic collection was updated on December 28, 2023 .

75 Stem Cell Essay Topic Ideas & Examples

🏆 best stem cell topic ideas & essay examples, ⭐ good research topics about stem cell, 👍 simple & easy stem cell essay titles.

• Stem Cell Research D, in the article I am Pro-Life and Oppose Embryonic Stem Cell Research, opposes stem cell research in particular embryonic stem cell research.
• Applying Neural Stem Cells to Counteract Brain Aging Pluripotent stem cells, or PSCs, are the best candidates for in vitro generation and cultivation of neural stem cells. Neural stem cells: Origin, heterogeneity and regulation in the adult mammalian brain.
• Stem Cells Applications in Bone and Tooth Repair and Regeneration It provides examples of scientific research about the application of stem cells in the process of the regeneration of bones and teeth.
• Ethical and Safety Issues of Stem Cell-Based Therapy Ilic and Ogilvie argue that this is a dilemma between the obligation of doctors and scientists to save lives and the need to destroy it in order to obtain stem cells.
• Blood Stem Cell Self-Renewal and Differentiation One of the distinct cells in the blood or hematopoietic stem cell. Due to this functionality, the blood and skin cells’ pose the greatest ability of differentiation and self-renewal.
• Embryonic Stem Cells and Nuclear Transfer Somatic cell dedifferentiation is the “direct reprogramming of an adult somatic cell to return to the state of a pluripotent stem cell” The pros of nuclear transfer are that these embryonic stem cells, which contain […]
• Stem Cell Regenerative Therapy This method is well-studied and has a proven track record of improving spinal stenosis, unlike stem cells. This evidence suggests that stem cells can potentially reverse the degeneration of bone and tissue.
• “What’s the Fuss about Stem Cells?” The primary goal of this essay is to emphasize the importance of the research of the stem cells, provide a precise definition, and explain their functions in the body.
• The Stem Cell Research: Key Aspects In light of the legal aspects of the research, the paper indicates that the human embryo deserves respect just as adults.
• Apple Stem Cell in Skincare Researchers have shown that extracts from Swiss apple, Malus domestica, have regenerative effect on skin, and thus have utilized them in the production of apple stem cells from adult cells.
• Stem Cell Research: Some Pros and Cons The science of stem cell treatments, potentially as or more significant than these other innovations, is beginning a new stage of exploration and growth that could be the forerunner of unprecedented cures and therapies.
• Stem Cells Biology: Features and Researchs Stem cells are cells that have the capacity to subdivide into other cells. The second property of stem cells is that they can develop into specialized cells in the differentiation process.
• Nanoscale Silver and Stem Cell Research Whether nanoscale silver or stem cell research, patients realize that the benefits of this technology go without saying. While silver provides many effective applications, stem cell research is the best alternative for curing pancreatic cancer.
• Stem Cell Research from Catholic Perspective The argument exists that because some embryos are created in petri dishes and require implantation into a womb to achieve their full potential that they should not be considered human life, and therefore, can be […]
• Ethics of Stem Cell Research Creating Superhumans Stem cell research is a subject that has generally been absent from the current public and political debates, pushed to the backburner by issues such as the economy, the Iraq War, healthcare, and immigration.
• Stem Cell Treatment, Its Benefits and Efficiency Stem cell treatment is a method that uses the transplantation of cells to facilitate the process of cell regeneration. In conclusion, stem cell therapy is expected to provide a breakthrough in the treatment of adverse […]
• A Promising Prognosis in Stem Cell Therapy The investigation of adult stem cells and induced pluripotent stem cells is of increasing interest as these cells have the most potential for the restoration of myocardial infarction-induced tissue damages.
• Stem Cell Therapy and Diabetes Medical Research This type of diabetes is less common and only occurs during the early stage when the immune system of the body attacks and destroys cells that produce insulin in the pancreas.
• Stem Cell Therapy in Colorectal Cancer The novel therapeutic methods used against colorectal cancer stem cells ranges from antibodies and antibody constructs to engineered nanoparticles that target cancerous stem cells in the colon.
• Factors That Influence Stem Cell Research For instance, the GDP of the United States measures the value of goods and services produced within the boundaries of the United States, by people living in the U.S.even if they are not American citizens. […]
• Using Embryonic Stem Cells to Grow Body Parts The use of embryonic stem cells is one of the important medical innovations of the 21st century. The process entails disassembling the embryo to get stem cells that are located in the internal parts of […]
• Kant’s Moral Philosophy on Stem Cell Research In Kant’s own words, “Autonomy of the will is the property that the will has of being a law to itself.[Morality] is the relation of actions to the autonomy of the will […].
• The Research and Use of Stem Cell Embryos Policies of governments across the globe vary on the legality of the prohibited and allowed research and use of stem cell embryos.
• Neural Stem Cells, Viral Vectors in Gene Therapy and Restriction Enzymes The nervous system is comprised of specialized type of cells called Neural Stem Cells. Developmental versatility of plasticity of neural stem cells is important in formation of these different neural cells.
• Stem Cell Research Implementation Nevertheless, the lack of adequate funding from the government has deteriorated the efforts of the researchers in embracing the benefits of this technology.
• Expanding Federal Government Funding of Stem Cell Research This is because stem cell research promises to cure degenerative diseases such as Alzheimer’s and scoliosis but the same time the cure requires the destruction of human embryonic stem cells that can only be had […]
• Adipose-Derived Mesenchymal Stem Cell Application Combined With Fibrin Matrix
• Embryonic Stem Cell Research Provides Revolutionary and Life-Saving Breakthroughs
• Immune Reconstitution After Allogeneic Hematopoietic Stem Cell Transplantation
• Ethical and Beneficial Replacement for Embryonic Stem Cell Research
• Biopsy Needle Advancement During Bone Marrow Aspiration and Mesenchymal Stem Cell Concentration
• Autoimmunity Following Allogeneic Hematopoietic Stem Cell Transplantation
• Bioinformatics Analysis and Biomarkers With Cancer Stem Cell Characteristics in Lung Squamous Cell Carcinoma
• Induced Pluripotent Stem Cell-Based Cancer Vaccines
• Embryonic Stem Cell Research: A New Paradigm in Medical Technology
• Advanced Functional Biomaterials for Stem Cell Delivery in Regenerative Engineering and Medicine
• Pragmatic Pluralism: Mutual Tolerance of Contested Understandings Between Orthodox and Alternative Practitioners in Autologous Stem Cell Transplantation
• Allogeneic Hematopoietic Stem Cell Transplantation in a Rare Case of Tonsillar Mast Cell Sarcoma
• Stem Cell Fate Determination During Development and Regeneration of Ectodermal Organs
• Biomimetic Extracellular Matrix Mediated Somatic Stem Cell Differentiation: Applications in Dental Pulp Tissue Regeneration
• Adult Stem Cell and Mesenchymal Progenitor Theories of Aging
• Ethical, Legal, and Social Issues in Genome or Stem Cell Research
• Defective Pulmonary Innate Immune Responses Post-stem Cell Transplantation
• Stem Cell Therapy for Diabetes
• Embryonic Stem Cell Research: The Pandora’s Box of Science
• Bone Marrow Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation
• Human Organ Culture: Updating the Approach to Bridge the Gap From in Vitro to in Vivo in Inflammation, Cancer, and Stem Cell Biology
• Adult Stem Cell Therapies for Wound Healing: Biomaterials and Computational Models
• Evaluating the Endocytosis and Lineage-Specification Properties of Mesenchymal Stem Cell-Derived Extracellular Vesicles for Targeted Therapeutic Applications
• Hematopoietic Stem Cell Transcription Factors in Cardiovascular Pathology
• Central Nervous System Complications in Children Receiving Chemotherapy or Hematopoietic Stem Cell Transplantation
• Christian Ethics and Embryonic Stem Cell Research
• Funding Stem Cell Research: A New Field of Innovative Medicine
• Mesenchymal Stem Cell-Derived Extracellular Vesicles in Aging
• Stem Cell Research and Its Effects on the Future of Medicine
• Developing Stem Cell-Based Therapies for Neural Repair
• Bioethical and Political Debates Surrounding Embryonic Stem Cell Research
• Autologous Hematopoietic Stem Cell Transplantation for Treatment of Systemic Sclerosis
• Mitochondrial Medicine: Genetic Underpinnings and Disease Modeling Using Induced Pluripotent Stem Cell Technology
• Dental Mesenchymal Stem Cell-Based Translational Regenerative Dentistry: From Artificial to Biological Replacement
• Embryonic Stem Cell Research Could Help Out Many People
• Zinc Maintains Embryonic Stem Cell Pluripotency and Multilineage Differentiation Potential via Akt Activation
• Human Liver Stem Cell-Derived Extracellular Vesicles Prevent Aristolochic Acid-Induced Kidney Fibrosis
• Stem Cell Therapy for Pediatric Traumatic Brain Injury
• Continuous Immune Cell Differentiation Inferred From Single-Cell Measurements Following Allogeneic Stem Cell Transplantation
• Stem Cell-Friendly Scaffold Biomaterials: Applications for Bone Tissue Engineering and Regenerative Medicine
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Articles on Stem cell research

Displaying 1 - 20 of 48 articles.

Triggering cancer cells to become normal cells – how stem cell therapies can provide new ways to stop tumors from spreading or growing back

Huanhuan Joyce Chen , University of Chicago Pritzker School of Molecular Engineering and Abhimanyu Thakur , University of Chicago Pritzker School of Molecular Engineering

Limits for human embryo research have been changed: this calls for public debate

Sheetal Soni , University of KwaZulu-Natal

New global guidelines for stem cell research aim to drive discussions, not lay down the law

Megan Munsie , The University of Melbourne and Melissa Little , Murdoch Children's Research Institute

The key to treating multiple sclerosis could be inside sufferers’ own bodies

Chris McMurran , University of Cambridge

First working eggs made from stem cells points to fertility breakthrough

Adam Watkins , Aston University

New autism research: a nutrient called carnitine might counteract gene mutations linked with ASD risks

Vytas A. Bankaitis , Texas A&M University and Zhigang Xie , Texas A&M University

Informed consent for stem cell research: why it matters and what you should know

Leslie Jacqueline Greenberg , University of Cape Town

How to make sure South Africa’s biobanks balance scientific progress with the law

Ames Dhai , University of the Witwatersrand and Safia Mahomed , University of the Witwatersrand

South Africa’s struggle to control sham stem cell treatments

Melodie Labuschaigne , University of South Africa and Michael Sean Pepper , University of Pretoria

Why the world needs to keep pace with breakthroughs in stem cell research

Marietjie Botes , University of Pretoria and Marco Alessandrini , University of Pretoria

Why South Africa needs better laws for stem cell research and therapy

Michael Sean Pepper , University of Pretoria ; Janine Scholefield , Council for Scientific and Industrial Research ; Melodie Labuschaigne , University of South Africa , and Robea Ballo , University of Cape Town

What lies behind the hype and the hope of stem cell research and therapy

Michael Sean Pepper , University of Pretoria and Nicolas Novitzky , University of Cape Town

A beginner’s guide to understanding stem cells

Michael Sean Pepper , University of Pretoria

Curing baldness may just be about having enough pluck

Cheng-Ming Chuong , University of Southern California

‘One of Us’ petition marks a sinister mobilisation of the pro-life movement in Europe

Sheelagh McGuinness , University of Birmingham and Heather Widdows , University of Birmingham

BAMI trial might provide bone marrow answers, but it won’t teach us much about stem cells

Jalees Rehman , University of Illinois Chicago

Opinions about scientific advances blur party-political lines

Matthew C. Nisbet , American University and Ezra Markowitz , Columbia University

Stem cells offer a more natural approach to plastic surgery

Ash Mosahebi , UCL

Biowire technology brings stem cells to life in human heart

University of Toronto

Dream of regenerating human body parts gets a little closer

James Godwin , Monash University

Related Topics

• African stem cells
• Embryonic stem cells
• Heart disease
• Informed consent
• Medical research
• Regenerative medicine
• Stem cell therapy

Top contributors

Director, Institute for Cellular and Molecular Medicine & SAMRC Extramural Unit for Stem Cell Research & Therapy, University of Pretoria

Professor and Former Program Leader of Stem Cells Australia, The University of Melbourne

Professor of Law, College of Law, University of South Africa

Research Group Leader, Stem Cells, CSIRO

Professor and Director, Centre for Genetic Diseases, Monash Institute of Medical Research, Monash University

Deputy Vice-Chancellor Academic Quality and Professor of Molecular Biology, UNSW Sydney

MB/PhD Candidate, University of Cambridge

Professor in Clinical Ethics, Macquarie University

Consultant, Cell Therapy and Genomics, University of Pretoria

Assistant Professor, University of Nottingham

Professor of Human Genetics: Stem Cell Researcher, University of Cape Town

John Ferguson Professor of Global Ethics, Department of Philosophy, University of Birmingham

Assistant Research Scientist, Texas A&M Health Science Center, Texas A&M University

Honorary Senior Lecturer, UCL

Professor of Tissue Development and Regeneration, University of Southern California

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• 10 breakthroughs in stem cell research

Stem cells could help cure heart failure. Christie Norris looks at major developments over the last three decades and the role the BHF is playing.

1989: The first “‘knockout”’ mouse

“Knockout” mice are bred to lack specific genes, which helps scientists find out which genes are linked to different diseases. By removing a particular gene, a disease similar to that seen in humans develops in the mouse. This helps scientists learn more about how diseases develop, what symptoms occur, and how they can be treated. The work of Mario Capecchi at the University of Utah, Oliver Smithies at the University of North Carolina and Martin Evans at Cardiff University led to the development of the first ‘knockout’ mouse in 1989 - they went on to be awarded the 2007 Nobel Prize in Physiology or Medicine.

 Knockout mice are now considered vital to disease research. Thanks to this discovery, BHF Professor Hugh Watkins, Director of the British Heart Foundation Centre of Research Excellence at Oxford University , is looking at genes associated with coronary heart disease .

1998: Embryonic stem cells

Our understanding of stem cells began with embryonic stem cells. They come from a ball of cells called the blastocyst, which forms five days after an egg is fertilised and develops into the embryo. Embryonic stem cells were isolated from mice in 1981.

In 1998, Professor James Alexander Thomson and his team at the University of Wisconsin–Madison grew the first human embryonic stem cells in a laboratory dish (in vitro). This allowed scientists to learn how the cells function.

Women who undergo IVF can donate ‘spare’ embryos, which would otherwise be destroyed. Only embryos at an early stage of development (up to 14 days) can be used, and there are strict guidelines for how they can be used.

2001: Making beating heart cells

In 2001, Professor Christine Mummery and her team in the Netherlands used stem cells to create beating heart cells outside the body for the first time. Her team is now working to grow a small piece of human heart from stem cells.

Stem cells could produce red blood cells for transfusion

This will let us study causes of diseases, especially genetic causes. It will also improve development of medicines that are usually tested on animals, as animal hearts work differently.

Researchers at the BHF Centres of Regenerative Medicine  are working to develop new treatments for diseased hearts. The centres are collaborations between top universities, including Edinburgh, Bristol, Oxford and Cambridge cardiac stem cells.

2002: Making new heart muscle

In 2002, researcher Chunhui Xu and team at Emory University School of Medicine in Atlanta found that human embryonic stem cells can be made to form heart muscle cells. This discovery encouraged scientists to explore whether embryonic stem cells could be used to make new heart muscle for heart attack patients. When a person has a heart attack, blood flow to the heart is restricted or blocked which can cause heart cells to die. Although less commonly used than other cell types, embryonic stem cells have helped researchers explore new ways of using stem cells to fix our hearts

2003: Discovery of cardiac stem cells 

Helping the heart regenerate itself after damage is a dream of cardiovascular researchers. Scientists thought the heart didn’t have its own stem cells, until Professor Antonio Beltrami at the University of Udine in Italy described a small population of stem cells in the heart in 2003.

Building on this discovery, BHF Professor Michael Schneider, at Imperial College London, is investigating how these stem cells can be ‘instructed’ to form new heart muscle, meaning the heart might be able to repair itself.

2004: Making heart cells from fats

In 2004, Valérie Planat-Bénard and colleagues at Paul Sabatier University in Toulouse, France, found that heart-like cells could be made from fat cells which lie just beneath the skin (adipose tissue). When compared to embryonic stem cells, fat cells are considered an easier and quicker means of making heart muscle cells in the lab

2007: Making heart cells from skin

In 2007, researcher Dr Shinya Yamanaka at Kyoto University found that human skin cells, which are easy to isolate, can be transformed directly into iPS cells.

Professor Sian Harding, at Imperial College London, is just one of the BHF-funded scientists using iPS cells as a resource to make new heart cells. We can use iPS cells to study inherited heart conditions.

The BHF is also funding Professor Chris Denning’s team at the University of Nottingham, which is growing cells from patients to examine how genetic mutations affect heart cell behaviour. Without stem cells, this work would only be possible using a biopsy of the patient’s heart.

2010: Waking up our hearts

Now that stem cells have been discovered in the heart, the challenge is to ‘wake them up’ so they’re ready to repair damage. BHF scientist Dr Nicola Smart, at the University of Oxford, has found new methods of ‘waking up’ the heart’s stem cells.

BHF researchers aim to cure heart failure by using stem cells to make new, healthy heart cells

She has shown that a protein called thymosin beta-4 can encourage cells to move towards damaged tissue and help form new muscle cells and blood vessels.

2013: Patches for damaged hearts 

Using bacteria sounds an unlikely way to grow new heart cells, but that’s exactly what Professor Ipsita Roy is doing. Professor Roy, from the University of Westminster, has developed bacteria-derived materials (polymers) that can be used inside the human body.

These polymers have been made into ‘patches’ with special coatings that encourage the growth of different types of cells. Researchers are now collaborating with cardiac surgeons to find the most effective ways of attaching these polymer patches onto areas of damaged heart muscle. Once there, the patch will repair the damage. Professor Roy is part of the  BHF-funded Centre of Regenerative Medicine that is led by Imperial College and focused on cardiac tissue engineering.

2016: New blood 

Researchers, led by Dr Jo Mountford of the Scottish National Blood Transfusion Service and the University of Glasgow, are scaling up generation of red blood cells from stem cells to make a limitless supply of clean blood for transfusion. This could help those who lose blood through surgery or injury.

What are stem cells?

The remaining unspecialised cells are adult stem cells. If damage occurs in certain parts of the body, they repair it by developing into the specific type of cell required. They can also replicate to produce more cells as needed. This happens naturally in some parts of the body, such as the intestine and bone marrow, but doesn’t generally happen in the heart.

Unfortunately, a heart attack , where oxygen supply to the heart is restricted, causes heart cells to die. This can lead to heart failure , a debilitating condition where the heart can no longer pump blood around the body as efficiently as it normally would.

Through our Mending Broken Hearts Appeal , BHF researchers aim to cure heart failure by using stem cells to make new, healthy heart cells.

Heart failure: a human problem

There are over half a million people in the UK living with heart failure, which is why we’re working so hard to find a cure.

Read Anne’s story on living with heart failure and get tips to help manage heart failure symptoms. You can also download our free Living with heart failure booklet at the BHF publications page.

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Study reveals the benefits and downside of fasting

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Low-calorie diets and intermittent fasting have been shown to have numerous health benefits: They can delay the onset of some age-related diseases and lengthen lifespan, not only in humans but many other organisms.

Many complex mechanisms underlie this phenomenon. Previous work from MIT has shown that one way fasting exerts its beneficial effects is by boosting the regenerative abilities of intestinal stem cells, which helps the intestine recover from injuries or inflammation.

In a study of mice, MIT researchers have now identified the pathway that enables this enhanced regeneration, which is activated once the mice begin “refeeding” after the fast. They also found a downside to this regeneration: When cancerous mutations occurred during the regenerative period, the mice were more likely to develop early-stage intestinal tumors.

“Having more stem cell activity is good for regeneration, but too much of a good thing over time can have less favorable consequences,” says Omer Yilmaz, an MIT associate professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the new study.

Yilmaz adds that further studies are needed before forming any conclusion as to whether fasting has a similar effect in humans.

“We still have a lot to learn, but it is interesting that being in either the state of fasting or refeeding when exposure to mutagen occurs can have a profound impact on the likelihood of developing a cancer in these well-defined mouse models,” he says.

MIT postdocs Shinya Imada and Saleh Khawaled are the lead authors of the paper, which appears today in Nature .

Driving regeneration

For several years, Yilmaz’s lab has been investigating how fasting and low-calorie diets affect intestinal health. In a 2018 study , his team reported that during a fast, intestinal stem cells begin to use lipids as an energy source, instead of carbohydrates. They also showed that fasting led to a significant boost in stem cells’ regenerative ability.

However, unanswered questions remained: How does fasting trigger this boost in regenerative ability, and when does the regeneration begin?

“Since that paper, we’ve really been focused on understanding what is it about fasting that drives regeneration,” Yilmaz says. “Is it fasting itself that’s driving regeneration, or eating after the fast?”

In their new study, the researchers found that stem cell regeneration is suppressed during fasting but then surges during the refeeding period. The researchers followed three groups of mice — one that fasted for 24 hours, another one that fasted for 24 hours and then was allowed to eat whatever they wanted during a 24-hour refeeding period, and a control group that ate whatever they wanted throughout the experiment.

The researchers analyzed intestinal stem cells’ ability to proliferate at different time points and found that the stem cells showed the highest levels of proliferation at the end of the 24-hour refeeding period. These cells were also more proliferative than intestinal stem cells from mice that had not fasted at all.

“We think that fasting and refeeding represent two distinct states,” Imada says. “In the fasted state, the ability of cells to use lipids and fatty acids as an energy source enables them to survive when nutrients are low. And then it’s the postfast refeeding state that really drives the regeneration. When nutrients become available, these stem cells and progenitor cells activate programs that enable them to build cellular mass and repopulate the intestinal lining.”

Further studies revealed that these cells activate a cellular signaling pathway known as mTOR, which is involved in cell growth and metabolism. One of mTOR’s roles is to regulate the translation of messenger RNA into protein, so when it’s activated, cells produce more protein. This protein synthesis is essential for stem cells to proliferate.

The researchers showed that mTOR activation in these stem cells also led to production of large quantities of polyamines — small molecules that help cells to grow and divide.

“In the refed state, you’ve got more proliferation, and you need to build cellular mass. That requires more protein, to build new cells, and those stem cells go on to build more differentiated cells or specialized intestinal cell types that line the intestine,” Khawaled says.

Too much of a good thing

The researchers also found that when stem cells are in this highly regenerative state, they are more prone to become cancerous. Intestinal stem cells are among the most actively dividing cells in the body, as they help the lining of the intestine completely turn over every five to 10 days. Because they divide so frequently, these stem cells are the most common source of precancerous cells in the intestine.

In this study, the researchers discovered that if they turned on a cancer-causing gene in the mice during the refeeding stage, they were much more likely to develop precancerous polyps than if the gene was turned on during the fasting state. Cancer-linked mutations that occurred during the refeeding state were also much more likely to produce polyps than mutations that occurred in mice that did not undergo the cycle of fasting and refeeding.

“I want to emphasize that this was all done in mice, using very well-defined cancer mutations. In humans it’s going to be a much more complex state,” Yilmaz says. “But it does lead us to the following notion: Fasting is very healthy, but if you’re unlucky and you’re refeeding after a fasting, and you get exposed to a mutagen, like a charred steak or something, you might actually be increasing your chances of developing a lesion that can go on to give rise to cancer.”

Yilmaz also noted that the regenerative benefits of fasting could be significant for people who undergo radiation treatment, which can damage the intestinal lining, or other types of intestinal injury. His lab is now studying whether polyamine supplements could help to stimulate this kind of regeneration, without the need to fast.

“This fascinating study provides insights into the complex interplay between food consumption, stem cell biology, and cancer risk,” says Ophir Klein, a professor of medicine at the University of California at San Francisco and Cedars-Sinai Medical Center, who was not involved in the study. “Their work lays a foundation for testing polyamines as compounds that may augment intestinal repair after injuries, and it suggests that careful consideration is needed when planning diet-based strategies for regeneration to avoid increasing cancer risk.”

The research was funded, in part, by a Pew-Stewart Trust Scholar award, the Marble Center for Cancer Nanomedicine, the Koch Institute-Dana Farber/Harvard Cancer Center Bridge Project, and the MIT Stem Cell Initiative.

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A new study led by researchers at MIT suggests that fasting and then refeeding stimulates cell regeneration in the intestines, reports Katharine Lang for Medical News Today . However, notes Lang, researchers also found that fasting “carries the risk of stimulating the formation of intestinal tumors.” 

Prof. Ömer Yilmaz and his colleagues have discovered the potential health benefits and consequences of fasting, reports Max Kozlov for Nature . “There is so much emphasis on fasting and how long to be fasting that we’ve kind of overlooked this whole other side of the equation: what is going on in the refed state,” says Yilmaz.

MIT researchers have discovered how fasting impacts the regenerative abilities of intestinal stem cells, reports Ed Cara for Gizmodo . “The major finding of our current study is that refeeding after fasting is a distinct state from fasting itself,” explain Prof. Ömer Yilmaz and postdocs Shinya Imada and Saleh Khawaled. “Post-fasting refeeding augments the ability of intestinal stem cells to, for example, repair the intestine after injury.” 

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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

Sequencing of human induced pluripotent stem cell lines highlights pervasive mutagenesis, heterogeneity between clones derived from the same individual during a single reprogramming experiment and positive selection for acquired mutations in BCOR .

• Foad J. Rouhani
• Xueqing Zou
• Serena Nik-Zainal

Pseudodynamic analysis of heart tube formation in the mouse reveals strong regional variability and early left–right asymmetry

Using high-resolution confocal images and computational surface mapping, Esteban et al. provide a detailed pseudodynamic atlas of early heart tube development (E7.5–E8.5), develop a morphometric staging system based on landmark curves and distances in the surface of the tissues and identify parameters that can be used for precise embryo staging across different labs. This morphometric analysis reveals early signs of left–right asymmetry, before the cardiac looping stage, which is regulated by the Nodal signaling pathway.

• Isaac Esteban
• Patrick Schmidt
• Miguel Torres

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

Destici, Zhu, et al. identify human-specific cis -regulatory elements (CREs) through a comparative epigenomic analysis of human and mouse cardiomyocytes at early stage of development and show that these CREs could contribute to species-specific cardiac features. Human-specific enhancers were particularly enriched in SNPs associated with human-specific traits (such as increased heart resting rate, atrial fibrillation and QRS duration), and the acquisition of human-specific enhancers could expand the functionality of the conserved transcriptional regulator ZIC3 by modifying its spatio-temporal expression.

• Eugin Destici
• Neil C. Chi

A single-cell comparison of adult and fetal human epicardium defines the age-associated changes in epicardial activity

Knight-Schrijver et al. use single-cell and single-nuclei RNA sequencing to profile the human fetal and adult epicardium in homeostatic conditions. The analysis shows fetal-specific epicardial gene programs that could support heart regeneration.

• Vincent R. Knight-Schrijver
• Hongorzul Davaapil
• Sanjay Sinha

Healthy cloned offspring derived from freeze-dried somatic cells

The development of safe preservation methods for genetic resources is important. Here, the authors successfully produce cloned mice from freeze-dried somatic cells, demonstrating the possibility of safe and low-cost preservation of genetic resources.

• Sayaka Wakayama
• Teruhiko Wakayama

Primate-specific transposable elements shape transcriptional networks during human development

The human genome harbors more than 4.5 million transposable element (TE)-derived insertions, the result of recurrent waves of invasion and internal propagation. Here they show that TEs belonging to evolutionarily recent subfamilies go on to regulate later stages of human embryonic development, notably conditioning the expression of genes involved in gastrulation and early organogenesis.

• Julien Pontis
• Cyril Pulver
• Didier Trono

Induced pluripotent stem cells of endangered avian species

iPSCs from three endangered avian species (including Okinawa rail, Japanese ptarmigan, and Blakiston’s fish owl) are developed and characterized as a potential resource for their conservation.

• Masafumi Katayama
• Tomokazu Fukuda
• Manabu Onuma

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Stem Cells and Ethics: Current Issues

Jennifer blair mccormick.

Departments of Medicine and Health Sciences Research, Bioethics Research Group, Mayo Clinic and College of Medicine, Rochester, MN 55905, USA

Holly A. Huso

Cardiovascular Surgery, Mayo Clinic and College of Medicine, Rochester, MN 55905, USA

Much attention has recently turned to the promise and potential of human stem cells in therapeutic applications for the repair of cardiac tissue. The advances being made in the laboratory are exciting, and the pace at which research using human stem cells is moving from bench to bedside is extraordinary. The social, ethical, and policy considerations embedded within this area of research also require a large amount of attention and deliberation so that the scientific progress is able to successfully continue without social backlash.

There is much attention being given to the promise and potential of human stem cells. Advances in the use of these cells in research are happening at an accelerating rate, and the findings in both fundamental biological research and translational and preclinical animal work is exciting. Embedded in the flurry of research activity, though, are several social, ethical, and policy considerations that also require as the attention being given to the science itself and the therapeutic applications in which it may result.

In situ, human stem cells have the ability to differentiate into a variety of cells types. Multipotent or adult stem cells are found in bone marrow, adipose, and neuronal tissue, among other places. Pluripotent, or embryonic, stem cells are found transiently in vivo in the developing embryo and were first isolated in vitro in 1998 [ 1 ]. The former can differentiate into a limited set of cell types while pluripotent stem cells can differentiate into all cell types derived from the three basic germ layers. Because of the multi/pluripotency of stem cells, researchers have spent much of the last decade or so intent on identifying ways to influence the differentiation of human stem cells into specific cell types. Through this work, scientists as well as the public hope to gain knowledge about basic biological processes, in particular, in development and differentiation and to development of potential therapies for use in the clinical setting as treatments for a number of devastating diseases and physiological traumas.

This area of research has not been without contentious political debate and social controversy in large part because of the source of human embryonic stem cells (hESC). Exciting work has been done to develop other means of creating pluripotent stem cells (e.g., parthenogenisis; [ 2 ]), blastomere biopsy [ 3 ], and induced pluripotency [ 4 , 5 ] to avoid the perceived moral issues associated with hESC. That said, there is general consensus within the scientific community [ 6 ] that research on all types of human stem cells—adult, embryonic, and those derived through induced pluripotency and parthenogenisis is critical to our understanding of development and other basic biological processes and of what therapeutic value human stem cells may provide.

Humans who have experienced a myocardial infarction or other cardiac injury are often left with a damaged area of their heart which cannot contract efficiently. Cardiac contractility depends on the function of involved cardiomyocytes. However, cardiomyocytes are incapable of cell division, which renders them quite useless once they have been damaged [ 7 ]. A deficit in healthy cardiomyocytes leads to the development or progression of heart failure. Thus, the regeneration and revascularization of cardiac muscle, a desirable therapeutic outcome, must occur at the myocardial level. This reality has shoved stem cells into the limelight of cardiovascular related research [ 8 ]. With the capability of differentiating into myocardial cells, stem cells can regenerate and revascularize damaged cardiac muscle.

Recently, there has been a focus on potential use of stem cells for treatment of a variety of diseased or damaged tissues, including cardiac tissue [ 9 – 11 ]. This work has occurred both in preclinical animal studies and early phase clinical trials with mesenchymal stem cells and hematopoietic stem cells, the latter of which have been used clinically for decades in the treatment of blood disorders. hESC and induced pluripotent stem (iPS) cells are also demonstrating promise with several research teams reporting successful in vitro differentiation of the stem cells into cells with cardiac phenotype in vitro and successful transplantation of these cells into animal models [ 12 ]. Others, in a proof-of-concept study, demonstrated using a murine model system that iPS cells created with human “stemness” factors successfully repaired myocardial infarction [ 13 ].

There are a number of ethical issues in stem cell research that merit discussion, each of significant importance, as we consider how the use of human stem cells will contribute to not only increasing our knowledge of basic and fundamental biological principles, but also how and if their use will reach clinical application. Here, we briefly discuss several pertinent ethical considerations related to stem cell research and therapy (see Table 1 .)

Ethical and Social Considerations

Access to materials.

Intellectual property rights (IPR) are sometimes overlooked in the debate over social and ethical considerations of deriving and using stem cells in research. However, given that these legal rights can dictate who can (or cannot) access certain materials and what constraints may govern the use of those materials, IPR are essential elements to consider in these discussions. The Wisconsin Alumni Research Foundation (WARF), the technology transfer and licensing arm of the University of Wisconsin, holds the patents for primate stem cell technology. These patents provide a broad reach that has led many to suggest that even with the loosening of restrictions granted to academic researchers, the patents will remain contentious because of the control they provide to WARF over commercial applications of hESC-based therapies [ 14 ]. In addition, both groups pioneering iPS cell technology, Shinya Yamanaka at Kyoto University and James Thomson at the University of Wisconsin, are applying for patents in Japan and the US, respectively. A third scientist, Kazuhiro Sakurada, Chief Scientific Officer at iZumi Bio, a biotechnology company in San Francisco, is also pushing forward with a patent application in Japan [ 15 ], which if granted would place IPR squarely in the hands of a for-profit entity. Regardless of the outcome, easy access and readily available materials are essential in any domain of research. How IPR will impact stem cell research will be determined in part by the scope of the patents granted as well as how scientists, biotech companies, and investors handle the barriers presented by IPR.

What is in the Dish

hESC lines are considered the gold standard for human stem cell research and therapy [ 16 ] and expertise and comparisons of other stem cells, including iPS cells, with hESC viewed as critical to advancements on all fronts [ 17 ]. Progress toward development of clinical applications of hESC is farther ahead than with iPS cells and as such, the first clinical trials using pluripotent stem cells are applying hESC technology [ 18 ]. Since there is a general agreement within the scientific community in order to reap their full potential, it is essential to push forward all types of stem cell research—using hESC and adult stem cells and pluripotent stem cells derived by other means, public debates around the source of hESC, and their use will not soon dissipate. The issues of when personhood begins and the inherent and perceived rights of an entity with the potential to become a person and how those compare to the rights of a person will continue to be a part of political and public dialog on stem cell research. While philosophers and religious scholars have debated these issues for hundreds of years, the nature of these debates, especially in the context of stem cell research, will hopefully shift away from the more recent contentious and politically controversial rhetoric, forcing people to “choose” sides. Beneficial outcomes will result if the conversation turns toward one in which individuals of differing views begin to listen to each other optimizing shared understanding and interpretation of societal concerns, values, and desired outcomes.

Returning Results and Predicting Future Use

Similar to researchers conducting genome wide association studies and creating biobanks [ 19 ], stem cell scientists will have to deal with issues linked to collecting and keeping tissue for future, unspecified use [ 20 ]. When tissue is collected from gamete, embryo, and somatic cell donors, genetic information is being collected. Genetic and genomic profiling of the tissue is important for research purposes, and if cell lines derived from the tissue may be used in clinical application, then medical histories linked to the tissue may also be important to collect. DNA itself is a unique identifier, and with a bit of additional personal information for each sample, the potential for individual identification is feasible generating concerns about privacy and confidentiality [ 21 – 24 ]. Additionally, what should occur if during the genomic analysis researchers discover a medically relevant finding that can be linked to an individual donor? Should that finding be returned to the individual and if so, how? Under what conditions ought such findings not be returned to donors? Donors currently satisfied with how the tissue they provide might be used may have moral or social objections to future uses that cannot be predicted at time of collection [ 20 , 25 , 26 ]. What kind of limitations on future use can donors request? Is there a level of uncertainty that donors will need to accept?

The points we have just briefly discussed do not lack in importance; however, there is an ethical and social concern that may not be receiving as much public scrutiny and discussion as some in the biomedical ethics and policy community believe it ought to receive. The safe translation of therapies resulting from stem cell research will be dependent in part on establishing efficient and efficacious regulatory oversight [ 27 ], as well as realistic expectations and timelines for clinical trials, and a truly authentic informed consent process.

Safe Translation

The potential for human stem cell research to lead to therapeutic applications for a number of devastating medical conditions has resulted in a situation not unique to stem cell research: high hope for cures and treatments for debilitating disease on the part of individuals and families affected by disease and much hype for quick and definitive success in finding these cures and treatments on the part of disease advocacy groups, stem cell research supporters, and scientists. The media often adds to this phenomenon by providing overenthusiastic and promising reports on scientific findings [ 28 ]. Political controversy surrounding hESC research has also added to making advancements with any type of stem cell in the context of disease of newsworthy interest.

The combination of the high hopes and hype can create a number of problematic situations: the disappointment in the inability of science to deliver quickly, pressures to move forward fast with clinical trials, and patients and families seeking—almost urgently, treatments and participating in clinical trials that may not meet safety and ethical standards [ 29 ]. The latter situation, sometimes referred to as “stem cell tourism,” is not new but is becoming more common as more applications using stem cells are pushed toward clinical trials [ 30 ]. Medical facilities often located in countries that lack the rigorous oversight found in the United States and many European countries advertise proven cures and treatments, luring patients overseas. The patients and their families sacrifice large sums of money; outcomes are unpredictable and have resulted in many times in either only temporary “fixes” or a worsening of the condition [ 30 , 31 ]. There is often no follow-up by the clinicians performing these procedures and upon return to their home country, patients present themselves to physicians who find themselves providing follow-up care for procedures that they may not endorse and for which they have no detailed background information.

The International Society of Stem Cell Research convened a task force in 2008 to address the concerns noted above [ 29 ]. The outcome was a set of guidelines issued at the end of that year. These guidelines are intended to provide a framework for use in the international research community for oversight and conduct of clinical trials, especially in the context of stem cell research. This document outlines the fundamental principles essential for the conduct of ethical and professional biomedical research: independent oversight and review, voluntary and authentic informed consent, and social justice and distribution.

Some commentators have pointed to history, noting that what derailed gene transfer research was a hope and hype phenomenon: scientists and other supporters were touting the technology to be a cure for many diseases and conditions [ 28 , 32 , 33 ]. Clinical trials were pushed forward, perhaps more quickly than they should have been, and when several tragic and well-publicized adverse events occurred, there was backlash. The FDA has granted approval for a few stem cell safety trials to begin, including one to StemCells, Inc. to test neuronal stem cells in treatment of a fatal pediatric condition—Batten's disease and another to Geron to test hESC in repair of spinal cord injury 1 . These are largely uncharted waters. Experts—both in the scientific and the biomedical ethics and policy communities, note that these trial approvals may be coming too soon. The Batten's disease trial will be done in children, which raises the regulatory issue of when and under what conditions it is appropriate to conduct pediatrics safety study (The Hastings Center Report, January to February; [ 34 ]). In the latter case, the preclinical data being used to justify the Geron trial has generated some discussion within the scientific community. The severity of the conditions of the animals used in these studies was not at the level many expect the clinical trial participants to have, and no large animal studies were done [ 18 ]. The reference to the gene transfer research is intended to be a cautionary reminder to scientists, patients, and other stem cell supporters. Let's not allow exciting advances, large levels of enthusiasm, and strong desires to help those who are ill hyperaccelerate the process. Research participants and their families need to be fully informed of all happenings from beginning to end. Transparency is a must and serves to benefit all involved.

Fully Informed

The consent process and ensuring that research participants are fully aware of risks and benefits and have sufficient information to make an autonomous decision, plagues all biomedical research. Lack of understanding on the part of trial enrollees can cause research participants to believe that they are receiving actual treatment for their conditions rather than partaking in a clinical trial. In fact, this concept of therapeutic misconception is often directly linked to faulty consent processes [ 35 ]. While not an issue unique to stem cell research, ensuring an authentic informed consent process for human stem cell trials will be key to avoiding a derailment experienced in gene transfer research.

In many cases, individuals first in line to participate in these trials—whether these trials are within the boundaries of US regulatory oversight or being held outside the US, are desperate for some treatment or cure. The participants are very ill and in some instances, the clinical trials present what many of these patients and their families perceive to be as their only option. This begs the question of whether these individuals (and their families, especially when the patient is a child) are vulnerable—whether each is able to make an independent and sufficiently informed decision about what is in his or her best interest. Many patients and their families are information seekers and tech-savvy and approach these trials armed with knowledge. That is, on one level they do fully comprehend that no therapeutic benefit may be achieved and in fact, potential harm is a very real risk; understand the likely necessity of foregoing current disease management and therapies to participate. They wish to participate to simply be doing something, if not directly for themselves, then at least others in the future. However, this does not remove the probability that there is an underlying hope that the direct benefit will be gained.

These concerns do not necessarily mean that we hold-off on human stem cell clinical trials. Rather, they suggest that scientists and ethics scholars ought to place an emphasis on truly understanding what an authentic consent process is and how to ensure that is what takes place all the time. This will require collaborative efforts to generate empirical data from studying current processes and determining patient expectations and comprehension needs. Fully understanding this dichotomy of motivation and how to balance it with fundamental ethical principles of human subjects research may facilitate how we look back on this period of biomedical research history.

No doubt, the excitement of research using human stem cells in repair of damaged cardiac tissue and other areas of regenerative medicine will continue. As the science moves from bench to bedside, it is just as important to give serious attention to the social, ethical, and policy considerations surrounding it. Completely resolving the issues we have raised may not be feasible, but moving discussion and work on them in parallel with the science is a necessity.

Acknowledgments

We gratefully acknowledge the assistance of M.R. Dickerson, D.J. Driscoll, and S.D. Sparks. We also thank our anonymous reviewers for their time and thoughtful comments. J.B. McC.'s work on this publication was made possible by Grant Number 1 UL1 RR024150-01* from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and the NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov/ . Information on Reengineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overviewtranslational.asp .

1 We note that at the time of this writing the FDA had placed a hold on the Geron Corporation trial. (New York Times, August 19 2009, page B8)

Contributor Information

Jennifer Blair McCormick, Departments of Medicine and Health Sciences Research, Bioethics Research Group, Mayo Clinic and College of Medicine, Rochester, MN 55905, USA.

Holly A. Huso, Cardiovascular Surgery, Mayo Clinic and College of Medicine, Rochester, MN 55905, USA.