BIOMATERIALS FOR STEM CELL DERIVED BETA CELL TRANSPLANTATION

项目总结

PROJECT SUMMARY Type 1 diabetes (T1D) is an autoimmune disease that can begin in childhood where the insulin-producing cells in the pancreas are destroyed. Some of the adverse effects of T1D that follow very high blood glucose levels are heart diseases, chronic wounds, and strokes. Individuals who suffer from T1D need to carefully monitor and control their blood glucose levels daily to survive, and the most common method is the injection of exogenous insulin. While this method does deliver insulin into the body and maintains blood glucose levels, the need for daily injections can be difficult to keep up with, physiological glucose dynamics are not completely restored, and there is a risk of hypoglycemia due to an excess of insulin. One of the most promising therapies in the past decade has been the transplantation of allogeneic pancreatic islets from cadaveric donors. While this method has made multiple patients be exogenous insulin-independent, this only lasts for about 5 years post- transplantation because most of the islets have poor engraftment, patients must undergo chronic immunosuppression, and there is limited donor supply. A strategy to provide a patient with a lifetime supply of insulin-producing cells that will have successful engraftment and prevent the need for chronic immunosuppression would be to deliver stem cell-derived insulin-producing cells in hydrogel carriers. Studies using this strategy so far have been able to successfully deliver these stem cell-derived cells encapsulated in natural polymer hydrogels such as alginate, but these cells do not fully integrate with the host, end up being rejected, and the use of natural polymers adds the risk of batch-to-batch variability, and low tunability and reproducibility. Synthetic polymer hydrogels, in contrast, have high tunability and reproducibility, and could ideally be used as a cell carrier and platform to culture and differentiate stem cells. The objective of this supplemental project is to engineer a synthetic polymer hydrogel with immobilized bioactive signals that can both direct the differentiation of pancreatic islets derived from stem cells, as well as deliver these cells to diabetic subjects. Aim 1: Engineer synthetic hydrogels that promote in vitro 3D survival, proliferation, differentiation of human stem cell- derived pancreatic progenitors into insulin-secreting immature β cells. Aim 2: Evaluate the ability of the engineered β cells delivered with novel hydrogels to restore normoglycemia in immunocompromised, diabetic mice.