Neural differentiation and transplantation of human and mouse embryonic stem cell-derived neural progenitors

Embryonic stem cells (ESCs) hold great promise both as a means to study neural development in vitro, due to their recapitulation of several key developmental processes, and as a source of clinically relevant cell types for use in cell replacement therapies for neurodegenerative diseases. In order to take full advantage of the therapeutic potential of ESCs, it is important to first study the progression from ESC to progenitor cell to differentiated neuron. Elucidation of the signaling programs and morphological events that occur during in vitro neural differentiation can allow for generation of efficient protocols for the enrichment of desired cell types. In addition, in vitro neural differentiation systems can serve as useful tools for the study of developmental events that are otherwise difficult to analyze in vivo. In vitro models of neural development can allow for manipulation of signaling pathways involved in neural specification and for the testing of candidate new drugs. My thesis is a compilation of work aimed at addressing key questions at each step of the process from ESC to transplantation of ESC-derived neural progenitors. First, I address the similarities observed between neural rosettes, structures observed during in vitro neurogenesis from ESCs, and the developing central nervous system. Next, I demonstrate efficient differentiation of human ESCs into ventral forebrain GABAergic interneuron progenitors and characterize their differentiation both in vitro and following transplantation into a mouse model of temporal lobe epilepsy. Lastly, I address the concern of tumor formation following transplantation of ESC-derived neural progenitors, which can result from residual undifferentiated pluripotent cells in the transplant cell population.