Upon differentiation, the expression of the transgene is dictated by the tissue-specific promoter, allowing the selection of the desired cell type, i. Examples of applications of mouse embryonic stem cells to repair or replace diseased tissues in animal models of human diseases. Address correspondence to Marisa E. Oxford University Press is a department of the University of Oxford.
Therapeutic applications of embryonic stem cells.
It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article navigation. Volume Article Contents. The World of Stem Cells. Human ES Cells. Role of Extracellular Factors. Embryonic Stem Cells: Oxford Academic.
Google Scholar. Jian Li. Esther Bettiol. Marisa E. The Journals of Gerontology: Article history. Split View Views. Cite Citation. Abstract The capacity of embryonic stem ES cells for virtually unlimited self renewal and differentiation has opened up the prospect of widespread applications in biomedical research and regenerative medicine. View large Download slide.
Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts.
Smith AG. Embryo-derived stem cells: Annu Rev Cell Dev Biol. Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Establishment in culture of pluripotential cells from mouse embryos. Donaldson DD, et al. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides.
Pease S, et al. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Retinoic acid accelerates embryonic stem cell-derived cardiac differentiation and enhances development of ventricular cardiomyocytes. J Mol Cell Cardiol. Hescheler J, Fleischmann BK. Lentini S, et al. Embryonic stem cells: Cardiovasc Res. Wiles MV, Keller G.
Multiple hematopoietic lineages develop from embryonic stem ES cells in culture. In vitro development of primitive and definitive erythrocytes from different precursors. Risau W, Sariola H. Zerwes HG, et al. Vasculogenesis and angiogenesis in embryonic-stem-cell-derived embryoid bodies. Embryonic stem cells and in vitro hematopoiesis. J Cell Biochem. Yamashita J, Itoh H. Hirashima M, et al.
Stem Cell Research
Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Embryonic stem cells express neuronal properties in vitro. Dev Biol. In vitro differentiation of embryonic stem cells into glial cells and functional neurons. J Cell Sci. Fuller SJ, et al. In vitro chamber specification during embryonic stem cell cardiogenesis.
Stem Cell Information
Expression of the ventricular myosin light chain-2 gene is independent of heart tube formation. J Biol Chem. Muscle cell differentiation of embryonic stem cells reflects myogenesis in vivo: Embryonic stem cell-derived chondrogenic differentiation in vitro: Mech Dev. Dani C, Smith AG. Dessolin S, et al. Differentiation of embryonic stem cells into adipocytes in vitro. Hepatic maturation in differentiating embryonic stem cells in vitro. FEBS Lett. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets.
Thomson JA, Kalishman J. Golos TG, et al. Isolation of a primate embryonic stem cell line. Derivation of pluripotent stem cells from cultured human primordial germ cells. Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol Med. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Multilineage differentiation from human embryonic stem cell lines.
Stem Cells. Feeder-free growth of undifferentiated human embryonic stem cells. Nat Biotechnol. Enrichment of neurons and neural precursors from human embryonic stem cells. Exp Neurol. Amit M, Itskovitz-Eldor J. Derivation and spontaneous differentiation of human embryonic stem cells.
J Anat. Endothelial cells derived from human embryonic stem cells. Hematopoietic colony-forming cells derived from human embryonic stem cells. Insulin production by human embryonic stem cells. Embryonic stem cell lines from human blastocysts: Kehat I, Kenyagin-Karsenti D. Snir M, et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest. Bianco P, Robey PG. Stem cells in tissue engineering.
From the cover: Induced neuronal differentiation of human embryonic stem cells. Brain Res.
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Neural progenitors from human embryonic stem cells. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Anderson DJ. Stem cells and pattern formation in the nervous system: Lillien L, Raphael H. Stem cell repair of central nervous system injury. J Neurosci Res. VEGF gene delivery to muscle: Mol Cell. Cell transplantation for the treatment of acute myocardial infarction using vascular endothelial growth factor-expressing skeletal myoblasts.
J Appl Physiol. Genetically selected cardiomyocytes from differentiating embryonic stem cells form stable intracardiac grafts. A fluorescent reporter gene as a marker for ventricular specification in ES-derived cardiac cells. Selection of ventricular-like cardiomyocytes from ES cells in vitro. O'Shea KS. Embryonic stem cell models of development. Anat Rec. Characterization of the expression of MHC proteins in human embryonic stem cells. Role of Fas ligand CD95L in immune escape: J Immunol. Westphal CH, Leder P. Curr Biol. Suicide gene transduction sensitizes murine embryonic and human mesenchymal stem cells to ablation on demand—a fail-safe protection against cellular misbehavior.
Gene Ther. Prospects for the use of nuclear transfer in human transplantation.
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Human therapeutic cloning. Nat Med. Solter D, Gearhart J. Putting stem cells to work. Viable offspring derived from fetal and adult mammalian cells. Embryonic and somatic cell cloning. Reprod Fertil Dev. Somatic cell nuclear transfer in humans: J Regener Med. The first human cloned embryo. Sci Am. Vogel G. Stem cell policy. Can adult stem cells suffice? Myoblast transplantation for heart failure. Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting.
Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Directed differentiation of embryonic stem cells into motor neurons. Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells.
Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Freed CR. Will embryonic stem cells be a useful source of dopamine neurons for transplant into patients with Parkinson's disease? Blastula-stage stem cells can differentiate into dopaminergic and serotonergic neurons after transplantation. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Myosin heavy chain gene expression in mouse embryoid bodies. An in vitro developmental study. Developmental analysis of tropomyosin gene expression in embryonic stem cells and mouse embryos.
Mol Cell Biol. Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circ Res. Development of cardiomyocytes expressing cardiac-specific genes, action potentials, and ionic channels during embryonic stem cell-derived cardiogenesis. Ann N Y Acad Sci. Stable fetal cardiomyocyte grafts in the hearts of dystrophic mice and dogs. Cellular cardiomyoplasty improves survival after myocardial injury. Cellular cardiomyoplasty in a transgenic mouse model.
Transplantation of embryonic stem cells improves cardiac function in postinfarcted rats. Natural history of fetal rat cardiomyocytes transplanted into adult rat myocardial scar tissue.
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Cardiomyocyte transplantation improves heart function. Ann Thorac Surg. Influence of embryonic cardiomyocyte transplantation on the progression of heart failure in a rat model of extensive myocardial infarction. Soria B. In-vitro differentiation of pancreatic beta-cells. Efrat S. Cell replacement therapy for type 1 diabetes. Trends Mol Med. Bortz WM, II. A conceptual framework of frailty: J Gerontol Med Sci. Morley JE. Anorexia, sarcopenia, and aging. Conceptualisation and measurement of frailty in elderly people. For example, karyotypic changes have been observed in several human ES cell lines after prolonged culture, and the rate at which these changes dominate a culture may depend on the culture method.
The status of imprinted genes can clearly change with culture conditions in other cell types. The ideal human ES cell medium, then, a would be cost-effective and easy to use so that many more investigators can use human ES cells as a research tool; b would be composed entirely of defined components not of animal origin; c would allow cell growth at clonal densities; and d would minimize the rate at which genetic and epigenetic changes accumulate in culture.
Such a medium will be a challenge to develop and will most likely be achieved through a series of incremental improvements over a period of years. Among all the newly derived human ES cell lines, twelve lines have gained the most attention. Human somatic nuclei were transferred into human oocytes nuclear transfer , which previously had been stripped of their own genetic material, and the resultant nuclear transfer products were cultured in vitro to the blastocyst stage for ES cell derivation.
Also, for some autoimmune diseases, such as type I diabetes, merely providing genetically-matched tissue will be insufficient to prevent immune rejection. Additionally, new human ES cell lines were established from embryos with genetic disorders, which were detected during the practice of preimplantation genetic diagnosis PGD. These new cell lines may provide an excellent in vitro model for studies on the effects that the genetic mutations have on cell proliferation and differentiation.
Papers published since this writing report defined culture conditions for human embryonic stem cells. See Ludwig et al. Biotech Papers published since the time this chapter was written address this: Both papers referenced in 30 and 31 were later retracted: As of this writing, 21 cell lines are currently available for distribution, all of which have been exposed to animal products during their derivation. Although it has been eight years since the initial derivation of human ES cells, it is an open question as to the extent that independent human ES cell lines differ from one another.
At the very least, the limited number of cell lines cannot represent a reasonable sampling of the genetic diversity of different ethnic groups in the United States, and this has consequences for drug testing, as adverse reactions to drugs often reflect a complex genetic component.
Once defined culture conditions are well established for human ES cells, there will be an even more compelling need to derive additional cell lines. One recent report now estimates hESC lines, see Guhr et al. The ability of ES cells to develop into all cell types of the body has fascinated scientists for years, yet remarkably little is known about factors that make one cell pluripotent and another more restricted in its developmental potential.
The transcription factor Oct4 has been used as a key marker for ES cells and for the pluripotent cells of the intact embryo, and its expression must be maintained at a critical level for ES cells to remain undifferentiated. Recently, two groups identified another transcription factor, Nanog, that is essential for the maintenance of the undifferentiated state of mouse ES cells.
By comparing gene expression patterns between different ES cell lines and between ES cells and other cell types such as adult stem cells and differentiated cells, genes that are enriched in the ES cells have been identified. Using this approach, Esg-1, an uncharacterized ES cell-specific gene, was found to be exclusively associated with pluripotency in the mouse. Since establishing human ES cells in , scientists have developed genetic manipulation techniques to determine the function of particular genes, to direct the differentiation of human ES cells towards specific cell types, or to tag an ES cell derivative with a certain marker gene.
Several approaches have been developed to introduce genetic elements randomly into the human ES cell genome, including electroporation, transfection by lipid-based reagents, and lentiviral vectors. While this technology is routinely used in mouse ES cells, it has recently been successfully developed in human ES cells See chapter 4: Genetically Modified Stem Cells , thus opening new doors for using ES cells as vehicles for gene therapy and for creating in vitro models of human genetic disorders such as Lesch-Nyhan disease.
RNA interference. RNAi can work efficiently in somatic cells, and there has been some progress in applying this technology to human ES cells. The pluripotency of ES cells suggests possible widespread uses for these cells and their derivatives. The ES cell-derived cells can potentially be used to replace or restore tissues that have been damaged by disease or injury, such as diabetes, heart attacks, Parkinson's disease or spinal cord injury.
The recent developments in these particular areas are discussed in detail in other chapters, and Table 1 summarizes recent publications in the differentiation of specific cell lineages. The differentiation of ES cells also provides model systems to study early events in human development. Because of possible harm to the resulting child, it is not ethically acceptable to experimentally manipulate the postimplantation human embryo. Therefore, most of what is known about the mechanisms of early human embryology and human development, especially in the early postimplantation period, is based on histological sections of a limited number of human embryos and on analogy to the experimental embryology of the mouse.
However, human and mouse embryos differ significantly, particularly in the formation, structure, and function of the fetal membranes and placenta, and the formation of an embryonic disc instead of an egg cylinder. In humans, the yolk sac also serves important early functions, including the initiation of hematopoiesis, but it becomes essentially a vestigial structure at later times or stages in gestation.
Similarly, there are dramatic differences between mouse and human placentas, both in structure and function. Thus, mice can serve in a limited capacity as a model system for understanding the developmental events that support the initiation and maintenance of human pregnancy. Human ES cell lines thus provide an important new in vitro model that will improve our understanding of the differentiation of human tissues, and thus provide important insights into processes such as infertility, pregnancy loss, and birth defects.
Human ES cells are already contributing to the study of development. For example, it is now possible to direct human ES cells to differentiate efficiently to trophoblast , the outer layer of the placenta that mediates implantation and connects the conceptus to the uterus. Cells resembling both oocytes and sperm have been successfully derived from mouse ES cells in vitro. Moreover, human ES cell studies are not limited to early differentiation, but are increasingly being used to understand the differentiation and functions of many human tissues, including neural, cardiac, vascular, pancreatic, hepatic, and bone see Table 1.
Moreover, transplantation of ES-derived cells has offered promising results in animal models. Although scientists have gained more insights into the biology of human ES cells since , many key questions remain to be addressed before the full potential of these unique cells can be realized. It is surprising, for example, that mouse and human ES cells appear to be so different with respect to the molecules that mediate their self-renewal, and perhaps even in their developmental potentials. But in conditions that would otherwise support undifferentiated proliferation, BMPs cause rapid differentiation of human ES cells.
Also, human ES cells differentiate quite readily to trophoblast, whereas mouse ES cells do so poorly, if at all. One would expect that at some level, the basic molecular mechanisms that control pluripotency would be conserved, and indeed, human and mouse ES cells share the expression of many key genes. Yet we remain remarkably ignorant about the molecular mechanisms that control pluripotency, and the nature of this remarkable cellular state has become one of the central questions of developmental biology.
Of course, the other great challenge will be to continue to unravel the factors that control the differentiation of human ES cells to specific lineages, so that ES cells can fulfill their tremendous promise in basic human biology, drug screening, and transplantation medicine. Faupel for proofreading this report. Page citation: Bethesda, MD: National Institutes of Health, U. Info Center. Figure 1.
Embryonic stem cell
Characteristics of Embryonic Stem Cells. The Promise of Stem Cell Research. Culture of ES Cells Mouse ES cells and human ES cells were both originally derived and grown on a layer of mouse fibroblasts called quot;feeder cellsquot; in the presence of bovine serum. Genetic Manipulation of ES Cells Since establishing human ES cells in , scientists have developed genetic manipulation techniques to determine the function of particular genes, to direct the differentiation of human ES cells towards specific cell types, or to tag an ES cell derivative with a certain marker gene.
Table 1. Establishment in culture of pluripotential cells from mouse embryos. Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Embryonic stem cell lines derived from human blastocysts. Cryopreserved embryos in the United States and their availability for research. Fertil Steril. Isolation of a primate embryonic stem cell line. Pluripotent cell lines derived from common marmoset Callithrix jacchus blastocysts. Biol Reprod. Bremer S, Hartung T. The use of embryonic stem cells for regulatory developmental toxicity testing in vitro —the current status of test development.
Curr Pharm Des. Embryonic stem cell-derived cardiac, neuronal and pancreatic cells as model systems to study toxicological effects. Toxicol Lett. Human embryonic stem cells develop into multiple types of cardiac myocytes: Circ Res. Differentiation of human embryonic stem cells to cardiomyocytes: Electrophysiological profiling of cardiomyocytes in embryonic bodies derived from human embryonic stem cells. BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways. Stem Cells. Maintenance of pluripotency in human embryonic stem cells is STAT3 independent.
Regulation of human embryonic stem cell differentiation by BMP-2 and its antagonist noggin. J Cell Sci. BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nat Biotechnol. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture.
Dev Biol. Feeder-free growth of undifferentiated human embryonic stem cells. Human feeder layers for human embryonic stem cells. Establishment and maintenance of human embryonic stem cell lines on human feeder cells derived from uterine endometrium under serum-free condition. Human feeders support prolonged undifferentiated growth of human inner cell masses and embryonic stem cells. Comparative evaluation of various human feeders for prolonged undifferentiated growth of human embryonic stem cells.
Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSKspecific inhibitor. Nat Med. Feeder layer - and serum-free culture of human embryonic stem cells. Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells.
Comparative genomic hybridization and karyotyping of human embryonic stem cells reveals the occurrence of an isodicentric X chromosome after long-term cultivation. Mol Hum Reprod. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Selective loss of imprinting in the placenta following preimplantation development in culture. Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst. Patient-specific embryonic stem cells derived from human SCNT blastocysts. Jun 17 ; Human embryonic stem cell lines with genetic disorders.
Reprod Biomed Online. Derivation, growth, and applications of human embryonic stem cells. Nat Genet. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Gene expression profiling of embryo-derived stem cells reveals genes associated with pluripotency and lineage specificity.
Genome Res. Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors. Molecular signature of human embryonic stem cells and its comparison with the mouse. Gene expression in human embryonic stem cell lines: Establishment of human embryonic stem cell-transfected clones carrying a marker for undifferentiated cells. Curr Biol. Stable genetic modification of human embryonic stem cells by lentiviral vectors.
Mol Ther. Efficient transfection of embryonic and adult stem cells. High-level sustained transgene expression in human embryonic stem cells using lentiviral vectors.