The loss of pancreatic beta-cells in type 1 diabetes results in absence of insulin secreted by the pancreas, and consequently elevated blood sugar which leads to various long-term complications. Diabetic patients would benefit tremendously from availability of transplantable replacement beta-cells. Much of current research focuses on producing beta-cells from stem cells. Despite some progress, it is at present still not possible to generate functional beta-cells in culture. The beta-like cells generated with current protocols in vitro lack key features of normal beta-cells, most notably the ability to secrete insulin a regulated manner. However, when stem cell-derived beta-cell precursors are transplanted into mice, they acquire properties of functional beta-cells, indicating that the precursors have the potential to transition into a mature beta-cell state.
This proposal explores strategies for maturing beta-cell precursors in the culture dish with the goal to produce fully functional insulin-producing beta-cells in vitro. Previous studies from our laboratory have resulted in a short list of candidate regulators of beta-cell maturation. We propose to manipulate these candidate regulators in vitro in order to force beta-cell precursors to adopt a mature phenotype. We have now established a robust in vitro system for culturing and manipulating beta-cell precursors. We have also generated and tested requisite reagents for manipulating precursors in the culture dish. Over the next year, we will obtain first results from these manipulations.