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      Deconstructing Stem Cell Tumorigenicity: A Roadmap to Safe Regenerative Medicine

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Many of the earliest stem cell studies were conducted on cells isolated from tumors rather than from embryos. Of particular interest was research on embryonic carcinoma cells (EC), a type of stem cell derived from teratocarcinoma. The EC research laid the foundation for the later discovery of and subsequent work on embryonic stem cells (ESC). Both ESC isolated from the mouse (mESC) and then later from humans (hESC) shared not only pluripotency with their EC cousins, but also robust tumorigenicity as each readily form teratoma. Surprisingly, decades after the discovery of mESC, the question of what drives ESC to form tumors remains largely an open one. This gap in the field is particularly serious as stem cell tumorigenicity represents the key obstacle to the safe use of stem cell-based regenerative medicine therapies. Although some adult stem cell therapies appear to be safe, they have only a very narrow range of uses in human disease. Our understanding of the tumorigenicity of human induced pluripotent stem cells (IPSC), perhaps the most promising modality for future patient-specific regenerative medicine therapies, is rudimentary. However, IPSC are predicted to possess tumorigenic potential equal to or greater than that of ESC. Here, the links between pluripotency and tumorigenicity are explored. New methods for more accurately testing the tumorigenic potential of IPSC and of other stem cells applicable to regenerative medicine are proposed. Finally, the most promising emerging approaches for overcoming the challenges of stem cell tumorigenicity are highlighted.

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          Most cited references 45

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          Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

          Differentiated cells can be reprogrammed to an embryonic-like state by transfer of nuclear contents into oocytes or by fusion with embryonic stem (ES) cells. Little is known about factors that induce this reprogramming. Here, we demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Unexpectedly, Nanog was dispensable. These cells, which we designated iPS (induced pluripotent stem) cells, exhibit the morphology and growth properties of ES cells and express ES cell marker genes. Subcutaneous transplantation of iPS cells into nude mice resulted in tumors containing a variety of tissues from all three germ layers. Following injection into blastocysts, iPS cells contributed to mouse embryonic development. These data demonstrate that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors.
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            Induced pluripotent stem cell lines derived from human somatic cells.

            Somatic cell nuclear transfer allows trans-acting factors present in the mammalian oocyte to reprogram somatic cell nuclei to an undifferentiated state. We show that four factors (OCT4, SOX2, NANOG, and LIN28) are sufficient to reprogram human somatic cells to pluripotent stem cells that exhibit the essential characteristics of embryonic stem (ES) cells. These induced pluripotent human stem cells have normal karyotypes, express telomerase activity, express cell surface markers and genes that characterize human ES cells, and maintain the developmental potential to differentiate into advanced derivatives of all three primary germ layers. Such induced pluripotent human cell lines should be useful in the production of new disease models and in drug development, as well as for applications in transplantation medicine, once technical limitations (for example, mutation through viral integration) are eliminated.
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              A bivalent chromatin structure marks key developmental genes in embryonic stem cells.

              The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific modification pattern, termed "bivalent domains," consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genes expressed at low levels. We propose that bivalent domains silence developmental genes in ES cells while keeping them poised for activation. We also found striking correspondences between genome sequence and histone methylation in ES cells, which become notably weaker in differentiated cells. These results highlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novel chromatin-based mechanism for maintaining pluripotency.
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                Author and article information

                Journal
                Stem Cells
                stem
                Stem Cells (Dayton, Ohio)
                Wiley Subscription Services, Inc., A Wiley Company
                1066-5099
                1549-4918
                May 2009
                : 27
                : 5
                : 1050-1056
                Affiliations
                [a ]simpleDepartment of Cell Biology and Human Anatomy & Stem Cell Program, University of California Davis School of Medicine Sacramento, California, USA
                [b ]simpleInstitute of Pediatric Regenerative Medicine, Shriners Hospital For Children Northern California Sacramento, California, USA
                Author notes
                Correspondence: Paul S. Knoepfler, Ph.D., e-mail: knoepfler@ 123456ucdavis.edu

                Author contributions: Paul Knoepfler contributed every aspect of the manuscript.

                First published online in S tem C ells Express February 12, 2009; available online without subscription through the open access option.

                Article
                10.1002/stem.37
                2733374
                19415771
                Copyright © 2009 AlphaMed Press

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                Categories
                Embryonic Stem Cells/Induced Pluripotent Stem Cells

                Molecular medicine

                safety, regenerative medicine, tumors, hesc, ipsc, stem cells

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