Embryonic Stem and Primordial Germ Cells Are Pluripotent

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Methods to isolate stem cells were first developed using animal models more than 20 years ago (Evans et al., 1981; Martin, 1981). Pluripotent stem cells are derived from either excess embryos (embryonic stem (ES) cells) or an aborted fetus (embryonic germ (EG) cells). To initiate an ES cell line, they must first be extracted from the inner cell mass (ICM) of a blastocyte (which contains about 30 cells with regenerative potential), cultured, passaged, and eventually maintained in vitro (see Figure 45.1). Similarly, primordial germ cells

Blastocyst

Figure 45.1 The Inner Cell Mass (ICM) of a human blastocyst is a source of embryonic stem cells. A blastocyst is derived from a embryo created by in vitro fertilization. The arrows denote the inner cell mass of the blastocyst found internal adjacent to the blastocoels (the hollow core). These 30 or so cells have the potential to become embryonic stem cells under proper culture conditions. If implanted into a receptive uterus, they have the potential to also become a fetus.

Figure 45.1 The Inner Cell Mass (ICM) of a human blastocyst is a source of embryonic stem cells. A blastocyst is derived from a embryo created by in vitro fertilization. The arrows denote the inner cell mass of the blastocyst found internal adjacent to the blastocoels (the hollow core). These 30 or so cells have the potential to become embryonic stem cells under proper culture conditions. If implanted into a receptive uterus, they have the potential to also become a fetus.

(obtained from a fetus) exhibit a similar developmental potential (Matsui et al., 1992). Stem cell lines provide the tools for unique investigations into the intrinsic and extrinsic controls of cell growth and differentiation (Guan et al., 2001; Wobus et al., 1997), signaling molecules and transduction pathways and transcription factors (Burdon et al., 2002) in stem cell biology. Stem cells have also been used to evaluate the cytotoxi-city of drugs, and this may provide a unique approach to assessing the safety of pharmaceuticals (Rohwedel et al., 2001).

New therapies are expected to be realized with the advent of ES cell culture that provides an unlimited source for stem cell therapy. The technology still has limitations in that transplantation of undifferentiated ES cells results in the formation of teratomas. Indeed, about 20% of the Parkinson rats developed teratoma-like tumors after transplantation of ES cells into the brain striatum of rats resulted in differentiation of domainergic cells improving motor asymmetry (Bjorklund et al., 2002). ES cell culture may circumvent the tumorgenic problem; nevertheless, a few contaminating undifferentiated ES cells could be problematic. Not surprisingly, with the technology available today, the tumorgenic potential of undifferentiated ES cells limits its rapid translation to human cell therapy.

The molecular controls of ES cell differentiation are poorly understood, but are thought to require growth factors to control differentiation during development (Schuldiner et al., 2000). The production of human ES and EG cells was reported in 1998 (Shamblott et al., 1998; Thomson et al., 1998). Culture of ES cells under conditions leading to the development of embryoid bodies

(EB) induces the differentiation of neural, dopaminergic, and glial elements (Brustle et al., 1999; Kim et al., 2002; Schuldiner et al., 2000), and insulin-secreting cells (Assady et al., 2001; Lumelsky et al., 2001), among others. Although the results in the mouse were not perfect (transplantation of the insulin-secreting cells did not produce a sustained correction of hyperglycemia in the engrafted animals), the islet-like clusters survive and secrete insulin in vivo. Other tissues generated from ES cell lines include mouse and human cardiomyocytes (Kehat et al., 2001; Maltsev et al., 1993; Wobus et al., 1997), hematopoietic cells (Kaufman et al., 2002; Nakano et al., 1996; Wiles et al., 1991), endothelial cells (Risau et al., 1988; Yamashita et al., 2000), skeletal muscles (Miller-Hance et al., 1993; Rohwedel et al., 1994), chondrocytes (Kramer et al., 2000), liver (Hamazaki et al., 2001), neural cells (Carpenter et al., 2001; Reubinoff et al., 2001; Zhang et al., 2001), and adipocytes (Dani et al., 1997). This will be discussed in detail later. Obviously, the potential for the development of new stem cell therapies is immense. Nevertheless, progress has been stymied by the availability of an insufficient number of fully functional cell lines.

Technical challenges remain concerning research using human ES cell lines. Although human ES cells and monkey ES cells are similar, there are significant differences between these primate models and their mouse counterparts. Some differences are as simple as their growth patterns (i.e., human ES cells grow in compact flat colonies, whereas murine ES cells form spherical colonies). Others include differences in protein expression. For example, human ES cells temporally express the embryonic antigens SSEA-3, SSEA-4, and SSEA-1 in a stage-specific manner upon differentiation; the order of expression is reversed in murine ES cells (Andrews et al., 1996; McLaren, 2001; Thomson et al., 1998). Due to these morphological and developmental differences, some investigators have called into question the applicability of murine models to human ES cell research.

Furthermore, after ES stem cell differentiation, transplantation of allogenic cells/tissues may be hindered by immunological incompatibility between the donor ES cells and the recipient. Admittedly, administration of immu-nosuppressive drugs prior to the transplantation is an option, but not without significant side effects. In the future, genetic alteration of histocompatibility gene expression may be an option, but presently research on this topic is sparse.

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