The treatment of a number of human disease states resulting from cell loss or cell dysfunction is limited by the lack of suitable cell populations for therapeutic transplantation. ES cell differentia tion is one potential source of transplantable cells for use as cell therapeutics. In combination the diverse differentiation potential, extensive proliferative capacity, and tractability for sophisticated genetic modification suggest that an ES cell population can be viewed as an unlimited number of any cells with any genetic constitution. Moreover, analysis of many of the cell populations produced from ES cells by differentiation has shown them to be not only representative of embryonic or adult populations by morphology and gene transcription, but also to share many functional characteristics and, in the case of progenitor and intermediate cells, manifest the appropriate developmental potential. The ability to form biologically functional cell populations in response to normal signaling pathways and via developmentally relevant intermediate populations suggests that ES cell differentiation is a superior route to the production of cells suited to integration, response and function within developing, developed, or diseased tissue.
Transplantation of ES cell-derived cell populations into normal and disease model animals has demonstrated the potential for these cells in disease control. ES-derived neurons and neural precursors (Brustle et al., 1999; McDonald et al., 1999; Arnhold et al., 2000; Kawasaki et al., 2000; Liu et al., 2000; Bjorkland et al., 2002), cardiomyocytes (Klug et al., 1996), mast cells (Tsai et al., 2000), and insulin-secreting cells (Soria et al., 2000) have been transplanted successfully into appropriate recipient sites and shown to survive; integrate; and, to some measurable extent, function within host tissue (Brustle et al., 1999; McDonald et al., 1999; Liu et al., 2000; Tsai et al., 2000; Bjorkland et al., 2002). For example, differentiating mouse ES cells and ES cell-derived neural precursors have been implanted to the brains of rats, into both ventricles and sites of solid tissue, and found to survive and incorporate into the recipient brain; migrate away from the site of injection; and differentiate to neurons, astrocytes, and oligodendrocytes (Brustle et al., 1997; Arnold et al., 2000). ES cell-derived glial precursors implanted to spinal cords of myelin-deficient rats differentiated to myelinating oligodendrocytes and astrocytes both at the site of injection and over a distance of several millimeters from the site of injection (Brustle et al., 1999; Liu et al., 2000). Similarly, integration and differentiation of human ES cell-derived neural precursors in the mouse brain has been demonstrated (Reubinoff et al., 2001; Zhang et al., 2001). By contrast, ES-derived hemo-poietic precursors have not been reported to integrate into the hemopoietic tissue of the host or rescue and repopulate lethally irradiated mice. This presumably reflects a failure of the differentiation environment in vitro to generate functional precursors for reconstituting adult hemapoiesis.
Functional recovery of disease model animals has been reported after implantation of ES cell-derived cell populations, providing important proof of concept for the projected applications of cell therapy. Differentiating ES cells have been implanted into the sites of cellular damage in rats with 6-ODHA lesions in the striatum, a model for Parkinson disease, where they integrated, differentiated appropriately to dopaminergic neurons; and, most important, reduced the phenotypic consequences of the lesion (Bjorklund et al., 2002). Behavioral recovery was accompanied by alterations in brain chemistry consistent with formation of functional dopaminergic neurons. Similarly, implantation of RA-induced ES cell-derived neural progenitors to sites of lesion in mechanically damaged spinal cords effected an improvement in locomotor function, consistent with differentiation of implanted cells to neurons, astrocytes, and oligodendrocytes (McDonald et al., 1999; Liu et al., 2000).
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