Generate Glucose-Responsive, Insulin-Producing Cells from Human Embryonic Stem Cells in 3D Cultures

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CBET-0756455YeThe objectives of this project are to develop a 3D human embryonic stem (hES) cell differentiation system and to elucidate the mechanisms of human pancreatogenesis through gene expression profiling and lineage tracing experiments. The specific aims are: (1) Establish a 3D collagen scaffolding hES cell culture system and demonstrate the generation of glucose-responsive, insulin-producing cells from hES cells in 3D cultures, and (2) Characterize the lineage-specific differentiation of hES cells into cells in 3D cultures. Initial studies will focus on in vitro experiments and subsequent studies will be designed to characterize in vivo functions of pancreatic cells in diabetic animal models through islet transplantation. Knowledge gained from these studies will be utilized to design a 3D culture system for directing the differentiation of hES cell into glucose-responsive and insulin-producing cells for islet transplantation. This is the next step to achieving the PI's long-term career goal of using 3D cultures to gain an understanding of biological behaviors of hES cells in 3D environments, which, in turn, will allow the designing of various 3D culture systems to direct lineage-specific hES cell differentiation into a variety of therapeutic cells for cell-based therapy. Findings from this work will offer new insights into hES cell biology, especially mechanisms that govern ES cell differentiation, proliferation, adhesion, migration, etc. in a 3D microenvironment. Technologies developed through this project will offer renewable cell sources for islet transplantation that can restore near-physiological insulin secretion capacity in type-1 or later stage type-2 diabetic patients. This project will also provide excellent opportunities for education and training of undergraduate and graduate students in stem cell engineering and regenerative medicine.