Embryonic stem cell differentiation: emergence of a new era in biology and medicine
Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA
The discovery of mouse embryonic stem (ES) cells >20 years ago represented a major advance in biology and experimental medicine, as it enabled the routine manipulation of the mouse genome. Along with the capacity to induce genetic modifications, ES cells provided the basis for establishing an in vitro model of early mammalian development and represented a putative new source of differentiated cell types for cell replacement therapy. While ES cells have been used extensively for creating mouse mutants for more than a decade, their application as a model for developmental biology has been limited and their use in cell replacement therapy remains a goal for many in the field. Recent advances in our understanding of ES cell differentiation, detailed in this review, have provided new insights essential for establishing ES cell-based developmental models and for the generation of clinically relevant populations for cell therapy.
[Keywords: ES cells; differentiation; mesoderm; endoderm; ectoderm; embryonic development]
GENES & DEVELOPMENT 19:1129-1155, 2005. © 2005 by Cold Spring Harbor Laboratory Press.
Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of blastocyst-stage embryos (Evans and Kaufman 1981; Martin 1981). Their importance to modern biology and medicine derives from two unique characteristics that distinguish them from all other organ-specific stem cells identified to date. First, they can be maintained and expanded as pure populations of undifferentiated cells for extended periods of time, possibly indefinitely, in culture. Unlike transformed tumor cell lines, ES cells can retain normal karyotypes following extensive passaging in culture. Second, they are pluripotent, possessing the capacity to generate every cell type in the body. The pluripotent nature of mouse ES cells was formally demonstrated by their ability to contribute to all tissues of adult mice, including the germline, following their injection into host blastocysts (Bradley et al. 1984). In addition to their developmental potential in vivo, ES cells display a remarkable capacity to form differentiated cell types in culture (Keller 1995; Smith 2001). Studies during the past 20 years have led to the development of appropriate culture conditions and protocols for the generation of a broad spectrum of lineages. The ability to derive multiple lineages from ES cells opens exciting new opportunities to model embryonic development in vitro for studying the events regulating the earliest stages of lineage induction and specification. Comparable studies are difficult in the mouse embryo and impossible in the human embryo. In addition to providing a model of early development, the ES cell differentiation system is viewed by many as a novel and unlimited source of cells and tissues for transplantation for the treatment of a broad spectrum of diseases. The isolation of human ES cells (hES) in 1998 dramatically elevated the interest in the cell therapy aspect of ES cells and moved this concept one step closer to reality (Thomson et al. 1998). This review details the current status of mouse and human ES cell differentiation from both the developmental biology and cell replacement perspectives. The first sections of the review highlight successes to date in the generation and characterization of mature populations, while the final section outlines the challenges for the future with a focus on the identification of progenitor cells representing the earliest stages of embryonic lineage development. The reader is referred to other recent reviews that provide additional details for many of the subjects covered here (Kyba and Daley 2003; Nir et al. 2003; Hornstein and Benvenisty 2004; Lang et al. 2004; Pera and Trounson 2004; Rippon and Bishop 2004; West and Daley 2004). For the purpose of this review, the term ES will be used in reference to mouse cells and hES for human cells.