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UCSD BGGN 231 - Embryonic Stem Cell Differentiation

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10.1101/gad.1303605Access the most recent version at doi: 2005 19: 1129-1155 Genes & Dev. Gordon Keller biology and medicineEmbryonic stem cell differentiation: emergence of a new era in References http://www.genesdev.org/cgi/content/full/19/10/1129#otherarticlesArticle cited in: http://www.genesdev.org/cgi/content/full/19/10/1129#ReferencesThis article cites 274 articles, 131 of which can be accessed free at: serviceEmail alerting click heretop right corner of the article or Receive free email alerts when new articles cite this article - sign up in the box at theTopic collections (61 articles) Development  (50 articles) Cancer and Disease Models  Articles on similar topics can be found in the following collections Notes http://www.genesdev.org/subscriptions/ go to: Genes and DevelopmentTo subscribe to © 2005 Cold Spring Harbor Laboratory Press on September 14, 2006 www.genesdev.orgDownloaded fromREVIEWEmbryonic stem cell differentiation:emergence of a new era in biologyand medicineGordon Keller1Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York 10029, USAThe discovery of mouse embryonic stem (ES) cells >20years ago represented a major advance in biology andexperimental medicine, as it enabled the routine ma-nipulation of the mouse genome. Along with the capac-ity to induce genetic modifications, ES cells provided thebasis for establishing an in vitro model of early mamma-lian development and represented a putative new sourceof differentiated cell types for cell replacement therapy.While ES cells have been used extensively for creatingmouse mutants for more than a decade, their applicationas a model for developmental biology has been limitedand their use in cell replacement therapy remains a goalfor many in the field. Recent advances in our under-standing of ES cell differentiation, detailed in this re-view, have provided new insights essential for establish-ing ES cell-based developmental models and for the gen-eration of clinically relevant populations for cell therapy.Embryonic stem (ES) cells are pluripotent cells derivedfrom the inner cell mass of blastocyst-stage embryos(Evans and Kaufman 1981; Martin 1981). Their impor-tance to modern biology and medicine derives from twounique characteristics that distinguish them from allother organ-specific stem cells identified to date. First,they can be maintained and expanded as pure popula-tions of undifferentiated cells for extended periods oftime, possibly indefinitely, in culture. Unlike trans-formed tumor cell lines, ES cells can retain normalkaryotypes following extensive passaging in culture. Sec-ond, they are pluripotent, possessing the capacity to gen-erate every cell type in the body. The pluripotent natureof mouse ES cells was formally demonstrated by theirability to contribute to all tissues of adult mice, includ-ing the germline, following their injection into host blas-tocysts (Bradley et al. 1984). In addition to their devel-opmental potential in vivo, ES cells display a remarkablecapacity to form differentiated cell types in culture(Keller 1995; Smith 2001). Studies during the past 20years have led to the development of appropriate cultureconditions and protocols for the generation of a broadspectrum of lineages. The ability to derive multiple lin-eages from ES cells opens exciting new opportunities tomodel embryonic development in vitro for studying theevents regulating the earliest stages of lineage inductionand specification. Comparable studies are difficult in themouse embryo and impossible in the human embryo. Inaddition to providing a model of early development, theES cell differentiation system is viewed by many as anovel and unlimited source of cells and tissues for trans-plantation for the treatment of a broad spectrum of dis-eases. The isolation of human ES cells (hES) in 1998 dra-matically elevated the interest in the cell therapy aspectof ES cells and moved this concept one step closer toreality (Thomson et al. 1998). This review details thecurrent status of mouse and human ES cell differentia-tion from both the developmental biology and cell re-placement perspectives. The first sections of the reviewhighlight successes to date in the generation and char-acterization of mature populations, while the final sec-tion outlines the challenges for the future with a focuson the identification of progenitor cells representing theearliest stages of embryonic lineage development. Thereader is referred to other recent reviews that provideadditional details for many of the subjects covered here(Kyba and Daley 2003; Nir et al. 2003; Hornstein andBenvenisty 2004; Lang et al. 2004; Pera and Trounson2004; Rippon and Bishop 2004; West and Daley 2004).For the purpose of this review, the term ES will be usedin reference to mouse cells and hES for human cells.Maintaining undifferentiated ES cellsES cells were initially established and maintained by co-culture with mouse embryonic feeder cells (Evans andKaufman 1981; Martin 1981). Subsequent studies iden-tified leukemia inhibitory factor (LIF) as one of thefeeder-cell-derived molecules that plays a pivotal role inthe maintenance of these cells (Smith et al. 1988; Wil-liams et al. 1988; Stewart et al. 1992). In the presence ofappropriate batches of fetal calf serum (FCS), recombi-nant LIF can replace the feeder cell function and sup-[Keywords: ES cells; differentiation; mesoderm; endoderm; ectoderm;embryonic development]1Correspondence.E-MAIL [email protected]; FAX (212) 803-6740.Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1303605.GENES & DEVELOPMENT 19:1129–1155 © 2005 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/05; www.genesdev.org 1129 on September 14, 2006 www.genesdev.orgDownloaded fromport the growth of undifferentiated ES cells (Smith et al.1988; Williams et al. 1988). Recently, Ying et al. (2003a)have uncovered a role for BMP4 in ES cell growth anddemonstrated that in the presence of LIF, it can replacethe requirement for serum. With these new develop-ments, it is now possible to grow ES cells with definedfactors in the absence of serum or feeder cells. Molecularanalyses have revealed that LIF functions through thegp130 activation of STAT3 (Niwa et al. 1998; Matsudaet al. 1999), whereas the effect of BMP4 on undifferenti-ated ES cells is mediated by Smad activation and thesubsequent induction of the helix–loop–helix Id factors.In addition to STAT3 and Id, two


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