(486g) Invited: Bioengineering of Pancreatic Islet Organoids from Hpscs

Type 1 diabetes results from the auto-immune destruction of inulin secreting cells of the pancreas – the beta cells within Islets of Langerhans. Exogenous supply of insulin is a commonplace procedure in regulating blood glucose levels in diabetic patients. Alternately, cell replacement therapies such as pancreas and islet transplants offer a more permanent solution to maintain blood glycemic control. However cell therapy is restricted by the availability of donor tissue, which can be overcome by deriving insulin producing cells from a regenerative cell source, like pluripotent stem cells (PSCs). With the current advancement of PSC-derived cell therapy from the laboratory to Phase 1 clinical trials, there is an enhanced emphasis on deriving mature and functional islets from hPSCs in a robust and reproducible manner. In parallel to regenerative therapy, there is also a strong emphasis to reproduce disease phenotypes in vitro, using microphysiology systems (MPS) models in tissue chip platforms. Once developed and validated, these models will be invaluable platforms for interrogating disease mechanisms as well as supplementing drug discovery and drug testing activities. The fundamental requirement of both the above stated applications of regenerative therapy and disease modeling in MPS is the successful derivation of mature and functional cells/ tissues/ organs from hPSCs.

Our research focuses on a range of tissue, organ and organoid engineering strategies for deriving pancreatic islet like cells from hPSCs. Our goal in this regard is to reproduce the cellular and structural components of pancreatic islet in the derived islet organoids, and thereby reproduce islet function. Towards this goal, we have developed cell encapsulation strategies for scalable culture of hPSCs and its subsequent differentiation to islet like clusters. We have explored the incorporation of organ specific extracellular matrices to enhance mature function of the derived islet like cells. In a collaborative team we have designed novel hydrogel substrate to synthesize controlled, multicellular organoids from hPSCs resembling pancreatic islets. We are currently developing strategies to induce in-vitro microvascular network formation within the stem cell derived islet organoids. This talk will highlight the strategies our lab is developing to engineer the cellular environment in order to closely mimic the natural islet environment. Our current efforts on integrating the derived islet organoids with MPS models for diabetes disease modeling will also be discussed.