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CONCISE REVIEW |
a Department of Surgery,
b Department of Medicine, and
c Department of Anatomy, University of Wisconsin School of Medicine, Madison, Wisconsin, USA;
d Wisconsin Regional Primate Research Center, Madison, Wisconsin, USA
Key Words. Embryonic stem cells • Transplantation • Human • Differentiation • Pluripotent
Correspondence:
Jon S. Odorico, M.D., Assistant Professor of Surgery, Department of Surgery, University of Wisconsin Hospital, H4/756 Clinical Science Center, 600 Highland Ave., Madison, Wisconsin 53792, USA. Telephone: 608-265-6471; Fax: 608-262-5624; e-mail: jon{at}tx.surgery.wisc.edu
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ABSTRACT |
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 Top Abstract IntroductionDerivation of Human ES...Properties of Human ES...Multilineage Differentiation In...Multilineage Differentiation In...Developing Transplantation...Preventing Immunologic Rejection...References |
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INTRODUCTION |
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TopAbstractIntroductionDerivation of Human ES...Properties of Human ES...Multilineage Differentiation In...Multilineage Differentiation In...Developing Transplantation...Preventing Immunologic Rejection...References |
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Although stem cells in adult tissues may have more "plasticity" than originally thought, they typically form only a limited number of cell types. Stem cells of the early mammalian embryo, in contrast, have the potential to form any cell type. In the unmanipulated blastocyst-stage embryo, stem cells of the inner cell mass (ICM) promptly differentiate to generate primitive ectoderm, which ultimately differentiates during gastrulation into the three embryonic germ (EG) layers. When removed from their normal embryonic environment and cultured under appropriate conditions, ICM cells give rise to cells that proliferate and replace themselves indefinitely. Yet, while in this undifferentiated state in culture, they maintain the developmental potential to form advanced derivatives of all three EG layers [2, 3]. ICM cells are the source cells from which pluripotent mouse, nonhuman primate, and human embryonic stem (ES) cells are generally derived, although there is evidence that mouse ES cells may be more closely related to primitive ectoderm [4-9].
The objective of this review is to describe the derivation and unique properties of human ES cells. Particular emphasis will be given to summarizing recent studies that focus on the potential of human ES cells for multilineage differentiation in vitro and in vivo. We will also outline key scientific questions that will need to be answered before the full therapeutic potential of human ES cells can be realized.
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DERIVATION OF HUMAN ES CELLS |
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TopAbstractIntroductionDerivation of Human ES...Properties of Human ES...Multilineage Differentiation In...Multilineage Differentiation In...Developing Transplantation...Preventing Immunologic Rejection...References |
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Human ES cells have been derived from the ICM of blastocyst-stage embryos in essentially the same manner as rhesus monkey ES cells [6, 7]. Cleavage-stage human embryos, produced by in vitro fertilization for clinical purposes, are donated by individuals after informed consent. After embryos are grown to the blastocyst stage, the ICM is isolated and plated onto mitotically inactivated murine embryonic fibroblast (MEF) feeder layers in tissue culture (Fig. 1
). The ICM cell outgrowths are propagated in the presence of serum, and colonies with the appropriate undifferentiated morphology are subsequently selected and expanded. After the initial derivation in serum, human ES cell lines can be maintained and propagated on feeder layers in medium containing serum alone or serum replacement medium and basic fibroblast growth factor (bFGF). Initially, human ES and EG cell lines were not clonally derived and so pluripotency could only be demonstrated for a population of cells. As such, the possibility existed that within a colony there were subpopulations of cells already committed to different lineages and no individual cell was capable of differentiating into derivatives of all three EG layers. Subsequently, clonally derived human ES cell lines, H9.1 and H9.2, were produced that retain all the properties of the parental ES cell line, including the ability to generate teratomas in vivo harboring derivatives of all three EG layers [16].
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PROPERTIES OF HUMAN ES CELLS |
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TopAbstractIntroductionDerivation of Human ES...Properties of Human ES...Multilineage Differentiation In...Multilineage Differentiation In...Developing Transplantation...Preventing Immunologic Rejection...References |
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Paralleling these differences in cellular morphology, human ES cells differ from their murine counterparts with regard to cell-surface antigen phenotype. Like undifferentiated primate ES cells and human EC cells, human ES cells express stage-specific embryonic antigens 3 and 4 (SSEA-3 and SSEA-4), high molecular weight glycoproteins TRA-1-60 and TRA-1-81, and alkaline phosphatase [7, 17]. Undifferentiated mouse ES cells do not express SSEA-3 or SSEA-4, but do express the lactoseries glycolipid SSEA-1, which is not expressed in human ES cells, rhesus ES cells, or human EC cells [7, 17]. The functional significance of these antigens is unknown.
Human ES cells also differ from mouse ES cells in their in vitro culture requirements for undifferentiated growth. Mouse ES cells require leukemia inhibitory factor (LIF) for undifferentiated proliferation. In contrast, LIF alone is not sufficient to prevent differentiation of human ES cells in vitro [7, 18]. Instead, continued undifferentiated propagation of human ES cells currently require feeder layers and either the presence of serum or, if cultured in serum-free medium, bFGF [7, 16]. Under conditions of low cell density, human ES cell lines are more difficult to propagate in serum, with a cloning efficiency of approximately 0.25% [16]. In contrast, culture in both serum replacement medium and supplemental bFGF significantly increases the cloning efficiency over culture in serum alone [16]. Fibroblast feeder layers are currently required to prevent differentiation of human ES cells. How undifferentiated proliferation can be sustained in the absence of feeder cells is an area of active investigation. The critical factors produced by fibroblast feeder layers, which prevent differentiation of human ES cells, are entirely unknown. Further work is clearly needed to clarify the mechanisms involved in sustaining human ES cell proliferation, including specific receptor-ligand interactions, downstream signaling events, and cellular target molecules. Ultimately, it would be essential to establish feeder-independent culture conditions, which permit large-scale propagation of human ES cells in culture.
Human ES cells have demonstrated remarkably stable karyotypes. Human ES cell lines demonstrate normal XX and XY karyotypes, similar to ES cell lines from other species, but distinct from human EC lines derived from teratocarcinomas [7]. This characteristic makes human ES cells more relevant as a model for the study of developmental biology mechanisms and for derivation of differentiated cells for transplantation therapy.
Human ES cells express high levels of telomerase. The expression of telomerase, a ribonucleoprotein that adds telomere repeats to chromosome ends, thereby maintaining their length, is highly correlated with immortality in human cell lines [19]. Most diploid somatic cells do not express high levels of telomerase and enter replicative senescence after a finite proliferative life span in tissue culture, usually after 50-80 population doublings. Unique among normal somatic cells, some populations of adult stem cells (i.e., hematopoietic stem cells) in vivo also constituitively express telomerase [20, 21]; however, telomerase activity is not sustained when cells are placed in culture. In contrast, cells of the early embryo have high telomerase activity levels [22, 23]. Likewise, human ES cell lines exhibit high telomerase activity levels even after more than 300 population doublings and passage for more than 1 year in culture [7, 16]. In summary, properties of cells of the early embryo, such as normal karyotype and high telomerase activity, are sustained for an extended period of time by human ES cell lines in culture. This unique property among human cell lines has important implications as a tool to study cellular senescence and mechanisms of stem cell renewal.
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MULTILINEAGE DIFFERENTIATION IN VITRO |
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TopAbstractIntroductionDerivation of Human ES...Properties of Human ES...Multilineage Differentiation In...Multilineage Differentiation In...Developing Transplantation...Preventing Immunologic Rejection...References |
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, B) [24]. As for mouse and nonhuman primate ES cells, differentiation in vitro is consistently disorganized and frequently variable from one EB to another within the same culture. A more comprehensive understanding of the morphology of human EBs and the relationships among different cell types comprising these complex embryo-like structures may yield important new information on early inductive events in human development.
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-fetoprotein and chorionic gonadotropin (CG) mRNA synthesis, and bioactive CG production [6]. Similarly, human EBs synthesize -fetoprotein transcripts and secrete -fetoprotein and hCG into the culture medium [7]. Human ES cells, therefore, represent a useful model in which to study human placental development and function. Mouse ES cell lines are able to differentiate in vitro into a variety of embryonic and adult cell types from all three EG layers. These include cardiomyocytes, hematopoietic progenitors, yolk sac, skeletal myocytes, smooth muscle cells, adipocytes, chondrocytes, endothelial cells, melanocytes, neurons, glia, pancreatic islet cells, and primitive endoderm [25-39]. From these experiments it is clear that ES cells induced to differentiate in culture follow many of the critical developmental stages found in the normal embryo, and are ultimately able to generate post-mitotic terminally differentiated cell types depending on the particular growth factor conditions.
As a result of their ability to differentiate into many different cell types, ES cells have been recognized as a valuable model system for studying the mechanisms underlying lineage specification during the early stages of mammalian development [25, 40, 41]. For example, by comparing downstream gene expression profiles between null mutant and wild-type ES cells, one can dissect the complex network of transcription factor genes regulating tissue-specific gene expression [42]. Also, in vitro culture provides a unique setting enabling control of the extrinsic cytokine or growth factor environment to study how these factors influence cellular differentiation [28, 31, 43]. Furthermore, in vitro differentiation of ES cells transduced with gene trap vectors can be used to discover novel developmentally regulated genes that are important in tissue-specific differentiation programs [44-47]. Thus, developmental pathways of cell lineages, which can be derived from ES cells, can be studied using this in vitro model system.
Recent studies demonstrate that human ES cells differentiating in culture are able to activate the expression of genes restricted to each of the three EG layers [18, 24, 43]. Human EBs derived from the human ES cell line, H9, transcribed genes for -fetoprotein, neurofilament 68kDa subunit, 
-globin, and -cardiac actin marking primitive endoderm, neuroectoderm, and mesoderm derivatives [24]. Differentiating cells acquired morphologies characteristic of neurons and cardiomyocytes [18, 24]. We have also performed human ES cell in vitro differentiation experiments. We observed that during subsequent development of plated EBs, cultures showed a variety of different morphologies, including rhythmically contracting cardiomyocytes, pigmented and non-pigmented epithelial cells, and neural cells displaying an exuberant outgrowth of axons and dendrites (Figs. 2C
, D). Regions within the differentiated cultures also contained cells having a mesenchymal morphology.
Schuldiner et al. supplemented these data and showed that both undifferentiated human ES cells and differentiated EBs expressed receptors for a number of different soluble growth factors with established effects on developmental pathways in vivo [43]. Addition of each of these growth factors individually to the culture medium altered the expression profile of an array of tissue-restricted genes [43]. However, none of these growth factors directed differentiation exclusively to one particular cell type [43]. A better understanding of the epigenetic events regulating cell lineage commitment and differentiation should permit the focused use of soluble growth factors to achieve lineage-restricted differentiation of human ES cells.
In other studies using human ES cells, we have used a co-culture method to promote hematopoietic differentiation. If human ES cells are allowed to differentiate on MEFs, hematopoietic colony-forming cells are not seen. In striking contrast, when the H1, H9, or clonal H1.1 human ES cell lines are co-cultured with irradiated mouse bone marrow stromal cells (S17 cells) in medium containing fetal bovine serum but no other exogenously added growth factors, they differentiate into a variety of cell types. The cell types derived under these conditions include cystic structures that resemble yolk sac, and cobblestone-type cells that are typical for hematopoietic precursors. CD34+ cells can be identified by flow cytometry, and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis shows induction of hematopoietic transcription factors. When human ES cells differentiated on S17 cells are harvested and placed in a methylcellulose colony-forming assay, a variety of hematopoietic colonies can be identified. These include colonies of erythroid, macrophage, granulocyte, and megakaryocyte cells (Figs. 2E, F). These data suggest that S17 bone marrow stromal cells either promote or support hematopoietic cell differentiation [48].
Endoderm lineages, such as pancreas and liver, are morphologically less distinct and more difficult to discern in ES cell cultures than blood or cardiac cells. This is one of the factors that has inhibited their detection among ES cell progeny. Differentiated ES cell progeny are able to express some endoderm and pancreas-restricted genes. Rhesus and mouse ES cells are capable of activating pancreatic and endoderm genes both in vitro and in vivo [38, 49]. Preliminary human ES cell gene expression studies show that differentiated derivatives of human ES cells can be induced to express endoderm genes, including hepatocyte nuclear factor 3 beta, and pancreatic islet genes including insulin, somatostatin, and glucagon (JSO, unpublished observations). Likewise, Schuldiner et al. recently presented RT-PCR gene expression data showing that differentiated progeny of human ES cells activate transcription of a variety of endoderm, liver, and pancreas-restricted genes [43]. However, it remains to be determined whether the initiation of pancreatic islet differentiation, as evidenced by gene transcription, will progress through a full differentiation program and lead to phenotypically adult islet cell populations with physiologic insulin secretion, as has been derived from mouse ES cells. Collectively, these data suggest that human ES cells can activate embryonic gene expression programs in culture and begin to differentiate into derivatives of all three EG layers.
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MULTILINEAGE DIFFERENTIATION IN VIVO |
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TopAbstractIntroductionDerivation of Human ES...Properties of Human ES...Multilineage Differentiation In...Multilineage Differentiation In...Developing Transplantation...Preventing Immunologic Rejection...References |
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) [7]. Easily identifiable differentiated cells in human ES cell teratomas include smooth muscle, striated muscle, bone, cartilage, fetal glomeruli, gut, respiratory epithelium, keratinizing squamous epithelium, hair, neural epithelium, and ganglia (Fig. 3). Compared with human EC cell lines, human ES cell lines exhibit both more advanced and more consistent developmental potential. For example, the human EC cell line NTERA2 c1.D1 injected into immunocompromised mice forms teratocarcinomas containing simple tubular structures resembling primitive gut, neural rosettes, and tissue resembling neuropile [10].
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DEVELOPING TRANSPLANTATION THERAPIES |
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TopAbstractIntroductionDerivation of Human ES...Properties of Human ES...Multilineage Differentiation In...Multilineage Differentiation In...Developing Transplantation...Preventing Immunologic Rejection...References |
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Although considerable progress in human transplantation medicine has been achieved in recent years, several major obstacles still restrict more widespread application of cellular transplantation in the routine treatment of these conditions. The chief obstacles that face this field are the need for massive doses of immunosuppressive drugs to prevent rejection of the transplanted tissue and the scarcity of organs from human cadaver donors. In light of these obstacles, a human ES cell-based strategy could permit the generation of an unlimited supply of cells or tissue from an abundant, renewable, and readily accessible source. Moreover, by virtue of their permissiveness for stable genetic modification, ES cells could be engineered to escape or inhibit host immune responses.
The first step toward successful development of a stem cell-based therapy for human diseases is to establish that human ES cells are capable of differentiating to a particular cell type of interest and to purify this lineage from the mixed population (Fig. 4). Unfortunately, the heterogeneous nature of development in culture has hampered the use of ES cell derivatives in transplantation studies. Rarely have specific growth factors or culture conditions led to establishment of cultures containing a single cell type [43, 65]. In fact, human pluripotent cell lines retain a broad pattern of multilineage gene expression despite the addition of specific growth factors [43, 65]. Furthermore, there is significant culture-to-culture variability in the developments of a particular phenotype under identical growth factor conditions. Given the broad range of lineages to which ES cells commit, derivation of a relatively homogeneous cell population will ultimately depend on selection from a mixed population of cells. One approach might involve using a tissue-specific promoter to drive a selectable marker such as an antibiotic resistance gene [38, 53, 54]. An alternative approach could involve transduction of a gene construct containing a tissue-specific promoter/enhancer controlling expression of a green fluorescence protein gene [66]. In this way, cells activating a lineage differentiation program of interest could be selected by fluorescence-activated cell sorting in much the same way that CD34+ hematopoietic stem cells are selected and sorted for stem cell transplantation. Both approaches would rely on the development of efficient gene transfer methodologies for human ES cells. A potential pitfall of these approaches is the concern for rejection of the transplanted cells which now express a foreign protein and the potential malignant transformation of genetically manipulated cells [67].
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A third major milestone on the road to clinical trials will be to demonstrate efficacy in rodent and large animal models of disease. Rhesus ES cells and the rhesus monkey provide an excellent preclinical model for developing ES cell-based transplantation therapies and for testing strategies to prevent immune rejection. Indeed, for Parkinson's disease and diabetes mellitus, good models are already available in the rhesus monkey [70, 71]. Achieving a therapeutic result will mandate integration of the transplanted cells into the host tissue in a functionally useful form. For example, replacing infarcted heart muscle or scar tissue with ES cell-derived cardiomyocytes will require that new muscle cells integrate with the existing muscle, contract in a coordinated and mechanically useful manner, and develop a new blood supply. Although complex structural integration would be essential for some cell transplants (e.g., neurons and cardiomyocytes), normal functioning of other ES cell-derived transplants will be more independent of such complex tissue interactions (e.g., islet cells and hematopoietic cells).
Fourth, the possibility arises that transplantation of differentiated human ES cell derivatives into human recipients may result in the formation of ES cell-derived tumors. From in vivo differentiation studies, it is clear that if undifferentiated rhesus or human ES cells are not rejected after implantation into host recipient animals, then a benign teratoma can result [6, 7]. These tumors are not metastatic, and do not rapidly kill the host animals. Tumor growth in immunodeficient animals appears to be dependent on the presence of a stem cell population in undifferentiated cultures. Thus, as ES cells are allowed to fully differentiate into post-mitotic, terminally differentiated derivatives, they should deplete the undifferentiated stem cell pools, thereby reducing the probability of uncontrolled tumor growth. In fact, from a limited number of short-term studies, it appears that transplanting differentiated progeny derived from murine ES cells into adult rodents does not result in significant tumor formation [38, 53, 57, 72]. However, these studies were not specifically designed to address this question, and as such, they lack sufficient animal numbers and long-term surveillance to allow firm conclusions. If tumor formation does depend on persistence of a stem cell population, then one could design a transgenic methodology to eliminate residual minority stem cells from differentiated ES cell cultures, possibly based on negative selection of Oct 4-expressing cells. Use of a positive selection transgene to achieve lineage-directed differentiation would also reduce the risk of tumor formation by selecting against the remaining undifferentiated, proliferating stem cell population. Irrespective of the persistence of stem cells, the possibility for malignant transformation of the derivatives will also need to be addressed. Ultimately, as the potential for tumor growth is a major safety consideration, a fail-safe method to prevent tumor growth may need to be developed. Once devised, strategies could be tested in a preclinical rhesus monkey model, using rhesus ES cell-derived cells, prior to embarking on human clinical trials.
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PREVENTING IMMUNOLOGIC REJECTION OF TRANSPLANTED CELLS |
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TopAbstractIntroductionDerivation of Human ES...Properties of Human ES...Multilineage Differentiation In...Multilineage Differentiation In...Developing Transplantation...Preventing Immunologic Rejection...References |
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) [73]. Currently available multidrug immunosuppressive regimens are effective in preventing rejection in most recipients of solid organ transplants. Even with a modest level of efficacy, a therapy brought to clinical trials for a disease with no other available treatment might still be considered a viable option, particularly if there were few repercussions of a failed transplant for the patient other than being returned to their baseline disease state. Unfortunately, however, currently used immunosuppressive drugs are far from ideal and are associated with numerous complications including wound healing, opportunistic infections, drug-related toxicities, skin malignancies, and low-grade lymphomas called post-transplant lymphoproliferative disorders. Instead, human ES cells could be genetically manipulated to reduce or eliminate immune-mediated rejection so that lifelong pharmacologic immunosuppression would not be required.
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Precisely how immunogenic is a cellular or tissue transplant from human ES cells? This may be a relevant question to ask as scientists attempt to engineer ES cells to reduce their immunogenicity. The immunogenicity of tissues is generally correlated with the MHC antigen expression profile and the relative abundance of antigen-presenting cells (e.g., dendritic cells) within the tissue. The MHC expression profile of human ES cell derivatives will depend on the degree of differentiation and/or the specific cell type derived. For example, adult somatic cells normally only express MHC class I antigens, whereas B cells, macrophages, and dendritic cells typically express both class I and class II antigens. Furthermore, whereas most adult organs and tissues harbor immunostimulatory dendritic cells and vascular endothelial cells, these normal tissue components would be expected to be absent from ES cell-derived cellular or tissue transplants. The specific removal of antigen-presenting cells from solid organ transplants generally increases graft survival [79, 80]. Consequently, some ES cell-derived tissues may be rather inert immunologically, while others, like hematopoietic stem cells, may be as immunogenic as normal adult tissues. Therefore, human ES cell-derived transplants may in some cases provide an inherent immunologic advantage compared to human cadaver tissue transplants.
Nuclear transfer technology may provide a more precise means to prevent rejection of transplanted cells (Fig. 5). This technique would lead to ES cell-derived cells that are an exact genetic match to the recipient. In this way, there should be minimal host immune response since all nuclear genes, including major and minor histocompatibility loci, would be seen as "self." Here, a nucleus would be extracted from a normal somatic cell of a patient, say from a skin biopsy, and then injected into an enucleated oocyte. Oocyte cytoplasm has the ability to reprogram differentiated nuclei, and as such, would reestablish an embryonic gene expression program in the chromatin of the somatic cell nucleus. A blastocyst developing from this oocyte would be a source for the derivation of a new ES cell line, which would be genetically matched for each nuclear gene of the patient. In this setting, the potential immune-mediated destruction of the graft would be limited to minor antigen differences derived from mitochondrial genes or to autoimmune processes, such as diabetes. Extending nuclear transfer technology to achieve the fusion of an entire cell with an enucleated oocyte might eliminate some of the remaining genetic differences that would exist between ES cell derivatives of nuclear transferred embryos and the prospective patient. In fact, in cows and mice, investigators have successfully combined nuclear transfer technology and ES cell derivation to establish transgenic ES cell lines from reprogrammed somatic cell nuclei [81]. Clearly though, the generation of human embryos by nuclear reprogramming to create novel human ES cell lines would be exceptionally controversial. Furthermore, the poor availability of human oocytes, the low efficiency of the nuclear transfer procedure, and the long population-doubling time of human ES cells make it difficult to envision this becoming a routine clinical procedure even if ethical considerations were not a significant point of contention. By studying how oocyte cytoplasm mediates nuclear reprogramming in these animal models, it might be likely that nuclear reprogramming could be achieved by other methods, thereby obviating the need for human oocytes.
Establishing hematopoietic chimerism is another potential means of preventing rejection of transplanted cells (Fig. 5). There are now many patients who have undergone bone marrow transplantation and subsequently received a solid organ transplant (typically a kidney) from the same donor as the bone marrow [82, 83]. In these circumstances, no immunosuppression is required for the solid organ transplant because the recipient's lymphocytes are from the same donor and have rendered the recipient immunologically tolerant. However, success of a bone marrow or hematopoietic stem cell transplant has generally required highly toxic immunosuppression. More recently, strategies have been designed which are significantly less myelotoxic while still permitting engraftment of donor hematopoietic stem cells [84]. This relatively mild treatment can permit long-term engraftment and could potentially allow successful solid organ transplantation in humans without prolonged immunosuppressive therapy. By using the same ES cell lines to derive both hematopoietic stem cells and other lineages, it may be possible to initially achieve hematopoietic chimerism followed by engraftment of a second cell type. Based on the principles described above, a second lineage should not be rejected as it would be regarded as "self" by the chimeric patient's bone marrow and immune system, which were derived, in part, from the same ES cell line. No long-term treatment with potentially toxic drugs would then be required. Ultimately, the rhesus monkey model will be essential for testing these and other strategies to prevent immune rejection.
Human ES cells fulfill all of the criteria of pluripotent ES cells. They are capable of indefinite self-renewal and multilineage differentiation, both in vivo and in vitro. This dual property provides the rationale for developing human ES cells as a basis for therapeutic tissue replacement. Not only do transplantation therapies based on ES cell-derived tissues offer the potential of overcoming limited tissue supplies, but they also present the exciting possibility of being able to perform tissue transplants with minimal or no immunosuppression.
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ACKNOWLEDGMENTS |
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TopAbstractIntroductionDerivation of Human ES...Properties of Human ES...Multilineage Differentiation In...Multilineage Differentiation In...Developing Transplantation...Preventing Immunologic Rejection...References |
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References |
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TopAbstractIntroductionDerivation of Human ES...Properties of Human ES...Multilineage Differentiation In...Multilineage Differentiation In...Developing Transplantation...Preventing Immunologic Rejection...References |
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L. Gruen and L. Grabel Concise Review: Scientific and Ethical Roadblocks to Human Embryonic Stem Cell Therapy Stem Cells, October 1, 2006; 24(10): 2162 - 2169. [Abstract] [Full Text] [PDF]
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 N. M. Walton, B. M. Sutter, H.-X. Chen, L.-J. Chang, S. N. Roper, B. Scheffler, and D. A. Steindler Derivation and large-scale expansion of multipotent astroglial neural progenitors from adult human brain Development, September 15, 2006; 133(18): 3671 - 3681. [Abstract] [Full Text] [PDF]
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X. Tian, P. S. Woll, J. K. Morris, J. L. Linehan, and D. S. Kaufman Hematopoietic Engraftment of Human Embryonic Stem Cell-Derived Cells Is Regulated by Recipient Innate Immunity Stem Cells, May 1, 2006; 24(5): 1370 - 1380. [Abstract] [Full Text] [PDF]
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J. Lu, R. Hou, C. J. Booth, S.-H. Yang, and M. Snyder Defined culture conditions of human embryonic stem cells PNAS, April 11, 2006; 103(15): 5688 - 5693. [Abstract] [Full Text] [PDF]
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Y. Guo, B. Graham-Evans, and H. E. Broxmeyer Murine Embryonic Stem Cells Secrete Cytokines/Growth Modulators That Enhance Cell Survival/Anti-Apoptosis and Stimulate Colony Formation of Murine Hematopoietic Progenitor Cells Stem Cells, April 1, 2006; 24(4): 850 - 856. [Abstract] [Full Text] [PDF]
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J. Cai, J. Chen, Y. Liu, T. Miura, Y. Luo, J. F. Loring, W. J. Freed, M. S. Rao, and X. Zeng Assessing Self-Renewal and Differentiation in Human Embryonic Stem Cell Lines Stem Cells, March 1, 2006; 24(3): 516 - 530. [Abstract] [Full Text] [PDF]
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 A. L. Olsen, D. L. Stachura, and M. J. Weiss Designer blood: creating hematopoietic lineages from embryonic stem cells Blood, February 15, 2006; 107(4): 1265 - 1275. [Abstract] [Full Text] [PDF]
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B. W. Sun, A. C. Yang, Y. Feng, Y. J. Sun, Y. f. Zhu, Y. Zhang, H. Jiang, C. L. Li, F. R. Gao, Z. H. Zhang, et al. Temporal and parental-specific expression of imprinted genes in a newly derived Chinese human embryonic stem cell line and embryoid bodies Hum. Mol. Genet., January 1, 2006; 15(1): 65 - 75. [Abstract] [Full Text] [PDF]
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 C. E. Murry, L. J. Field, and P. Menasche Cell-Based Cardiac Repair: Reflections at the 10-Year Point Circulation, November 15, 2005; 112(20): 3174 - 3183. [Full Text] [PDF]
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 P. S. Woll, C. H. Martin, J. S. Miller, and D. S. Kaufman Human Embryonic Stem Cell-Derived NK Cells Acquire Functional Receptors and Cytolytic Activity J. Immunol., October 15, 2005; 175(8): 5095 - 5103. [Abstract] [Full Text] [PDF]
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 L. Vallier, M. Alexander, and R. A. Pedersen Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells J. Cell Sci., October 1, 2005; 118(19): 4495 - 4509. [Abstract] [Full Text] [PDF]
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 A. Leri, J. Kajstura, and P. Anversa Cardiac Stem Cells and Mechanisms of Myocardial Regeneration Physiol Rev, October 1, 2005; 85(4): 1373 - 1416. [Abstract] [Full Text] [PDF]
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S. A. Przyborski Differentiation of Human Embryonic Stem Cells After Transplantation in Immune-Deficient Mice Stem Cells, September 1, 2005; 23(9): 1242 - 1250. [Abstract] [Full Text] [PDF]
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Y. Guo, G. Hangoc, H. Bian, L. M. Pelus, and H. E. Broxmeyer SDF-1/CXCL12 Enhances Survival and Chemotaxis of Murine Embryonic Stem Cells and Production of Primitive and Definitive Hematopoietic Progenitor Cells Stem Cells, September 1, 2005; 23(9): 1324 - 1332. [Abstract] [Full Text] [PDF]
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T. Li, S. Wang, Y. Xie, Y. Lu, X. Zhang, L. Wang, S. Yang, D. Wolf, Q. Zhou, and W. Ji Homologous Feeder Cells Support Undifferentiated Growth and Pluripotency in Monkey Embryonic Stem Cells Stem Cells, September 1, 2005; 23(8): 1192 - 1199. [Abstract] [Full Text] [PDF]
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 A Vats, N S Tolley, A E Bishop, and J M Polak Embryonic stem cells and tissue engineering: delivering stem cells to the clinic J R Soc Med, August 1, 2005; 98(8): 346 - 350. [Full Text] [PDF]
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H. Chen, K. Qian, J. Hu, D. Liu, W. Lu, Y. Yang, D. Wang, H. Yan, S. Zhang, and G. Zhu The derivation of two additional human embryonic stem cell lines from day 3 embryos with low morphological scores Hum. Reprod., August 1, 2005; 20(8): 2201 - 2206. [Abstract] [Full Text] [PDF]
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M. Qin, G. Tai, P. Collas, J. M. Polak, and A. E. Bishop Cell Extract-Derived Differentiation of Embryonic Stem Cells Stem Cells, June 1, 2005; 23(6): 712 - 718. [Abstract] [Full Text] [PDF]
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R. Behr, C. Heneweer, C. Viebahn, H.-W. Denker, and M. Thie Epithelial-Mesenchymal Transition in Colonies of Rhesus Monkey Embryonic Stem Cells: A Model for Processes Involved in Gastrulation Stem Cells, June 1, 2005; 23(6): 805 - 816. [Abstract] [Full Text] [PDF]
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 G. Keller Embryonic stem cell differentiation: emergence of a new era in biology and medicine Genes & Dev., May 15, 2005; 19(10): 1129 - 1155. [Abstract] [Full Text] [PDF]
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A. M. Wobus and K. R. Boheler Embryonic Stem Cells: Prospects for Developmental Biology and Cell Therapy Physiol Rev, April 1, 2005; 85(2): 635 - 678. [Abstract] [Full Text] [PDF]
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T. Ezashi, P. Das, and R. M. Roberts Low O2 tensions and the prevention of differentiation of hES cells PNAS, March 29, 2005; 102(13): 4783 - 4788. [Abstract] [Full Text] [PDF]
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P. Stojkovic, M. Lako, R. Stewart, S. Przyborski, L. Armstrong, J. Evans, A. Murdoch, T. Strachan, and M. Stojkovic An Autogeneic Feeder Cell System That Efficiently Supports Growth of Undifferentiated Human Embryonic Stem Cells Stem Cells, March 1, 2005; 23(3): 306 - 314. [Abstract] [Full Text] [PDF]
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C. Xu, E. Rosler, J. Jiang, J. S. Lebkowski, J. D. Gold, C. O'Sullivan, K. Delavan-Boorsma, M. Mok, A. Bronstein, and M. K. Carpenter Basic Fibroblast Growth Factor Supports Undifferentiated Human Embryonic Stem Cell Growth Without Conditioned Medium Stem Cells, March 1, 2005; 23(3): 315 - 323. [Abstract] [Full Text] [PDF]
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 C. Coraux, B. Nawrocki-Raby, J. Hinnrasky, C. Kileztky, D. Gaillard, C. Dani, and E. Puchelle Embryonic Stem Cells Generate Airway Epithelial Tissue Am. J. Respir. Cell Mol. Biol., February 1, 2005; 32(2): 87 - 92. [Abstract] [Full Text] [PDF]
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 S. Kodama, M. Davis, and D. L. Faustman Diabetes and Stem Cell Researchers Turn to the Lowly Spleen Sci. Aging Knowl. Environ., January 19, 2005; 2005(3): pe2 - pe2. [Abstract] [Full Text]
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 J. B. Lee, J. E. Lee, J. H. Park, S. J. Kim, M. K. Kim, S. I. Roh, and H. S. Yoon Establishment and Maintenance of Human Embryonic Stem Cell Lines on Human Feeder Cells Derived from Uterine Endometrium under Serum-Free Condition Biol Reprod, January 1, 2005; 72(1): 42 - 49. [Abstract] [Full Text] [PDF]
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C. Xu, J. Jiang, V. Sottile, J. McWhir, J. Lebkowski, and M. K. Carpenter Immortalized Fibroblast-Like Cells Derived from Human Embryonic Stem Cells Support Undifferentiated Cell Growth Stem Cells, November 1, 2004; 22(6): 972 - 980. [Abstract] [Full Text] [PDF]
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 M. Stojkovic, M. Lako, T. Strachan, and A. Murdoch Derivation, growth and applications of human embryonic stem cells Reproduction, September 1, 2004; 128(3): 259 - 267. [Abstract] [Full Text] [PDF]
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K. A. Buytaert-Hoefen, E. Alvarez, and C. R. Freed Generation of Tyrosine Hydroxylase Positive Neurons from Human Embryonic Stem Cells after Coculture with Cellular Substrates and Exposure to GDNF Stem Cells, September 1, 2004; 22(5): 669 - 674. [Abstract] [Full Text] [PDF]
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M. Stojkovic, M. Lako, P. Stojkovic, R. Stewart, S. Przyborski, L. Armstrong, J. Evans, M. Herbert, L. Hyslop, S. Ahmad, et al. Derivation of Human Embryonic Stem Cells from Day-8 Blastocysts Recovered after Three-Step In Vitro Culture Stem Cells, September 1, 2004; 22(5): 790 - 797. [Abstract] [Full Text] [PDF]
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K. A. Hohenstein and D. H. Shain Changes in Gene Expression at the Precursor -> Stem Cell Transition in Leech Stem Cells, July 1, 2004; 22(4): 514 - 521. [Abstract] [Full Text] [PDF]
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 D. Rudy-Reil and J. Lough Avian Precardiac Endoderm/Mesoderm Induces Cardiac Myocyte Differentiation in Murine Embryonic Stem Cells Circ. Res., June 25, 2004; 94(12): e107 - e116. [Abstract] [Full Text] [PDF]
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X. Zeng, T. Miura, Y. Luo, B. Bhattacharya, B. Condie, J. Chen, I. Ginis, I. Lyons, J. Mejido, R. K. Puri, et al. Properties of Pluripotent Human Embryonic Stem Cells BG01 and BG02 Stem Cells, May 1, 2004; 22(3): 292 - 312. [Abstract] [Full Text] [PDF]
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B. Bhattacharya, T. Miura, R. Brandenberger, J. Mejido, Y. Luo, A. X. Yang, B. H. Joshi, I. Ginis, R. S. Thies, M. Amit, et al. Gene expression in human embryonic stem cell lines: unique molecular signature Blood, April 15, 2004; 103(8): 2956 - 2964. [Abstract] [Full Text] [PDF]
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A. T. Clark, M. S. Bodnar, M. Fox, R. T. Rodriquez, M. J. Abeyta, M. T. Firpo, and R. A. R. Pera Spontaneous differentiation of germ cells from human embryonic stem cells in vitro Hum. Mol. Genet., April 1, 2004; 13(7): 727 - 739. [Abstract] [Full Text] [PDF]
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 B. C. Heng, H. K. Haider, E. K.-W. Sim, T. Cao, and S. C. Ng Strategies for directing the differentiation of stem cells into the cardiomyogenic lineage in vitro Cardiovasc Res, April 1, 2004; 62(1): 34 - 42. [Abstract] [Full Text] [PDF]
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S.-P. Park, Y. J. Lee, K. S. Lee, H. A. Shin, H. Y. Cho, K. S. Chung, E. Y. Kim, and J. H. Lim Establishment of human embryonic stem cell lines from frozen-thawed blastocysts using STO cell feeder layers Hum. Reprod., March 1, 2004; 19(3): 676 - 684. [Abstract] [Full Text] [PDF]
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 E. Ribourtout and J. Raymond Gene Therapy and Endovascular Treatment of Intracranial Aneurysms Stroke, March 1, 2004; 35(3): 786 - 793. [Abstract] [Full Text] [PDF]
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D. S. Kaufman, R. L. Lewis, E. T. Hanson, R. Auerbach, J. Plendl, and J. A. Thomson Functional endothelial cells derived from rhesus monkey embryonic stem cells Blood, February 15, 2004; 103(4): 1325 - 1332. [Abstract] [Full Text] [PDF]
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S. Levenberg, N. F. Huang, E. Lavik, A. B. Rogers, J. Itskovitz-Eldor, and R. Langer Differentiation of human embryonic stem cells on three-dimensional polymer scaffolds PNAS, October 28, 2003; 100(22): 12741 - 12746. [Abstract] [Full Text] [PDF]
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 M. Korbling and Z. Estrov Adult Stem Cells for Tissue Repair -- A New Therapeutic Concept? N. Engl. J. Med., August 7, 2003; 349(6): 570 - 582. [Full Text] [PDF]
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 W. P. Cheshire Jr, E. D. Pellegrino, L. K. Bevington, C. B. Mitchell, N. L. Jones, K. T. Fitzgerald, C. E. Koop, and J. F. Kilner Stem Cell Research: Why Medicine Should Reject Human Cloning Mayo Clin. Proc., August 1, 2003; 78(8): 1010 - 1018. [PDF]
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K. Hochedlinger and R. Jaenisch Nuclear Transplantation, Embryonic Stem Cells, and the Potential for Cell Therapy N. Engl. J. Med., July 17, 2003; 349(3): 275 - 286. [Full Text] [PDF]
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M. Ruhnke, H. Ungefroren, G. Zehle, M. Bader, B. Kremer, and F. Fandrich Long-Term Culture and Differentiation of Rat Embryonic Stem Cell-Like Cells into Neuronal, Glial, Endothelial, and Hepatic Lineages Stem Cells, July 1, 2003; 21(4): 428 - 436. [Abstract] [Full Text] [PDF]
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T. Nakamura and M. D. Schneider The Way to a Human's Heart Is Through the Stomach: Visceral Endoderm-Like Cells Drive Human Embryonic Stem Cells to a Cardiac Fate Circulation, June 3, 2003; 107(21): 2638 - 2639. [Full Text] [PDF]
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H.-C. Kuo, K.-Y. F. Pau, R. R. Yeoman, S. M. Mitalipov, H. Okano, and D. P. Wolf Differentiation of Monkey Embryonic Stem Cells into Neural Lineages Biol Reprod, May 1, 2003; 68(5): 1727 - 1735. [Abstract] [Full Text] [PDF]
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A. Sachinidis, B. K. Fleischmann, E. Kolossov, M. Wartenberg, H. Sauer, and J. Hescheler Cardiac specific differentiation of mouse embryonic stem cells Cardiovasc Res, May 1, 2003; 58(2): 278 - 291. [Abstract] [Full Text] [PDF]
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S. G. Nir, R. David, M. Zaruba, W.-M. Franz, and J. Itskovitz-Eldor Human embryonic stem cells for cardiovascular repair Cardiovasc Res, May 1, 2003; 58(2): 313 - 323. [Abstract] [Full Text] [PDF]
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R. Passier and C. Mummery Origin and use of embryonic and adult stem cells in differentiation and tissue repair Cardiovasc Res, May 1, 2003; 58(2): 324 - 335. [Abstract] [Full Text] [PDF]
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M. J. Goldenthal and J. Marin-Garcia Stem cells and cardiac disorders: an appraisal Cardiovasc Res, May 1, 2003; 58(2): 369 - 377. [Abstract] [Full Text] [PDF]
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K. Johkura, L. Cui, A. Suzuki, R. Teng, A. Kamiyoshi, S. Okamura, S. Kubota, X. Zhao, K. Asanuma, Y. Okouchi, et al. Survival and function of mouse embryonic stem cell-derived cardiomyocytes in ectopic transplants Cardiovasc Res, May 1, 2003; 58(2): 435 - 443. [Abstract] [Full Text] [PDF]
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 Q. He, J. Li, E. Bettiol, and M. E. Jaconi Embryonic Stem Cells: New Possible Therapy for Degenerative Diseases That Affect Elderly People J. Gerontol. A Biol. Sci. Med. Sci., March 1, 2003; 58(3): M279 - 287. [Abstract] [Full Text] [PDF]
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F. Nishimura, M. Yoshikawa, S. Kanda, M. Nonaka, H. Yokota, A. Shiroi, H. Nakase, H. Hirabayashi, Y. Ouji, J.-I. Birumachi, et al. Potential Use of Embryonic Stem Cells for the Treatment of Mouse Parkinsonian Models: Improved Behavior by Transplantation of In Vitro Differentiated Dopaminergic Neurons from Embryonic Stem Cells Stem Cells, March 1, 2003; 21(2): 171 - 180. [Abstract] [Full Text] [PDF]
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J. D. Down and M. E. White-Scharf Reprogramming Immune Responses: Enabling Cellular Therapies and Regenerative Medicine Stem Cells, January 1, 2003; 21(1): 21 - 32. [Abstract] [Full Text] [PDF]
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L. Gepstein Derivation and Potential Applications of Human Embryonic Stem Cells Circ. Res., November 15, 2002; 91(10): 866 - 876. [Abstract] [Full Text] [PDF]
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 D. E. Redmond Jr. Book Review: Cellular Replacement Therapy for Parkinson's Disease--Where We Are Today? Neuroscientist, October 1, 2002; 8(5): 457 - 488. [Abstract] [PDF]
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 H. Preclikova, V. Bryja, J. Pachernik, P. Krejci, P. Dvorak, and A. Hampl Early Cycling-independent Changes to p27, Cyclin D2, and Cyclin D3 in Differentiating Mouse Embryonal Carcinoma Cells Cell Growth Differ., September 1, 2002; 13(9): 421 - 430. [Abstract] [Full Text] [PDF]
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 I. Kuehnle and M. A Goodell The therapeutic potential of stem cells from adults BMJ, August 17, 2002; 325(7360): 372 - 376. [Full Text] [PDF]
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K. R. Boheler, J. Czyz, D. Tweedie, H.-T. Yang, S. V. Anisimov, and A. M. Wobus Differentiation of Pluripotent Embryonic Stem Cells Into Cardiomyocytes Circ. Res., August 9, 2002; 91(3): 189 - 201. [Abstract] [Full Text] [PDF]
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A. Shiroi, M. Yoshikawa, H. Yokota, H. Fukui, S. Ishizaka, K. Tatsumi, and Y. Takahashi Identification of Insulin-Producing Cells Derived from Embryonic Stem Cells by Zinc-Chelating Dithizone Stem Cells, July 1, 2002; 20(4): 284 - 292. [Abstract] [Full Text] [PDF]
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S. Levenberg, J. S. Golub, M. Amit, J. Itskovitz-Eldor, and R. Langer Endothelial cells derived from human embryonic stem cells PNAS, April 2, 2002; 99(7): 4391 - 4396. [Abstract] [Full Text] [PDF]
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T. Yamada, M. Yoshikawa, S. Kanda, Y. Kato, Y. Nakajima, S. Ishizaka, and Y. Tsunoda In Vitro Differentiation of Embryonic Stem Cells into Hepatocyte-Like Cells Identified by Cellular Uptake of Indocyanine Green Stem Cells, March 1, 2002; 20(2): 146 - 154. [Abstract] [Full Text] [PDF]
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T. Yamada, M. Yoshikawa, M. Takaki, S. Torihashi, Y. Kato, Y. Nakajima, S. Ishizaka, and Y. Tsunoda In Vitro Functional Gut-Like Organ Formation from Mouse Embryonic Stem Cells Stem Cells, January 1, 2002; 20(1): 41 - 49. [Abstract] [Full Text] [PDF]
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J. Rossant Stem Cells from the Mammalian Blastocyst Stem Cells, November 1, 2001; 19(6): 477 - 482. [Abstract] [Full Text]
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S. Levenberg, J. S. Golub, M. Amit, J. Itskovitz-Eldor, and R. Langer Endothelial cells derived from human embryonic stem cells PNAS, April 2, 2002; 99(7): 4391 - 4396. [Abstract] [Full Text] [PDF]
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