Disease and injury strike every organ in our body, killing and damaging cells that perform vital functions. How to replenish the lost cells and repair organ function is the outstanding question in regenerative medicine. Our laboratory pioneered a new path for tissue regeneration. Based on principles of development, we identified master regulators that dictate the formation of specific cells (pancreatic beta-cells and intestine stem cells) and by modulating the expression of these master genes, one can remake, or reprogram existing adult cells from one type to another, thereby regenerating medically important cell types.
We have used a cocktail of three pancreatic beta-cell master regulators, Ngn3, Pdx1, and Mafa, to reprogram pancreatic acinar cells or stomach epithelial cells to insulin-secreting cells that are capable of replacing pancreatic beta-cells for regulating blood sugar levels. Following up on these studies, some of the projects in the lab include 1) use primary human gut stem cells to derive insulin-secreting cells for transplantation therapy for diabetes, 2) gain mechanistic understanding of how master regulators reprogram cells, 3) model Type 1 diabetes, an autoimmune disease using gut-derived insulin-secreting cells, vascular cells, and immune cells.
We study the gut stem cells with a particular focus on understanding their regional differences and regeneration. We have identified master regulators that distinguish the small intestine from the large intestine. Modulating expression of these factors in gut stem cells leads to rapid reprogramming from large intestine epithelium to small intestine epithelium or vice versa. The questions we are addressing include 1) How do the gut master regulators maintain the distinct molecular and functional differences between gut regions? 2) What are the roles that these factors play in adaptive intestinal changes such as the short-bowel disease, digestive failure, and inflammatory bowel disease? 3) Can we develop small molecule modulators of these master genes as therapeutics to treat digestive failure and inflammatory bowel disease?