Adult central nervous system (CNS) neurons fail to regenerate following injury, and there is no repair or replacement of cells lost after injury or in neurodegenerative diseases. There is much interest in transplanting stem cell-derived neurons into the injured nervous system and enhancing the differentiation of donor cells into mature, integrated and functional neurons. Little is known, however, about what signals control the differentiation and integration of neurons, either during development or in the adult. Generating appropriate types of donor neurons from stem cells has been challenging because the signals that regulate neural subtype-specific fates are largely unknown. Therefore, it remains unclear what instructive signals work in parallel with the RGC-permissive transcription factor Math5 to control RGC fate specification. Here we report a new molecular pathway involving Sox4/Sox11 in parallel to GDF-11/Math5 signaling that is required for RGC differentiation from RPCs in vitro and in vivo and sufficient to potentiate the differentiation of electrophysiologically active human RGCs from induced pluripotent stem (iPS) cells. We further describe regulation of Sox4 by REST and the TGFβ family member GDF-15, and SUMOylation-dependent regulation of compensatory Sox11 activity by Sox4. Through this work we also uncovered a mechanism for SUMOylation regulation of Sox11 localization and function. These data define a novel molecular network necessary and sufficient for RGC fate specification and suggest a pro-RGC molecular manipulation which may provide potential promise for cell replacement-based therapies.
My other work focused on the challenges of translating my findings on RGC cell fate specficiation in mouse to more clinically relevant models. For example, I made progress developing methodologies for the in vitro derivation of RGCs from both human ciliary margin biopsy samples and from human induced pluripotent stem cells. I further demonstrated the capcity of RGCs to integrate into the retina following transplantation in vivo and made progress in improving delivery methods using hydorgell to mimic extracellular environments. Taken together, my work represents a multi-prong approach towards advancing RGC stem based-therapies towards the clinic.
- stem cells,
Available at: http://works.bepress.com/jonathan_hertz/1/