Available: 10/01/18, Expires: 05/01/22
Diabetes mellitus is a worldwide, ever-growing epidemic. Even though there have been incredible advances in the management of diabetes in recent years, a more permanent treatment for diabetes mellitus has remained elusive. Using genetic techniques and directed differentiation with small molecules, the scientific community has managed to create beta cells from multiple stem cell types; however, important issues remain regarding their viability, host immune response, risk for neoplasia as well ethical concerns. By using a patient’s own adult stem cells, one may be able to bypass these issues. Gastrointestinal (GI) stem cells are plentiful in mature gut, are easily accessible via endoscopy, and can be readily expanded and differentiated ex vivo into mature cell types, including enteroendocrine cells (EECs), which secrete incretin hormones that increase insulin release with food intake, in three-dimensional structures known as enteroids. Moreover, proof-of-principle studies in mice have shown that EE cells can be efficiently reprogrammed into insulin-secreting beta-like cells upon introduction of key beta cell transcription factors. Our preliminary studies show that human EE cells can be reprogrammed into insulin-expressing cells, albeit with reduced efficiency compared to the murine studies.
This project seeks to examine the ability of GI stem cells to produce incretin-secreting and insulin-secreting cells through small molecules. We anticipate that this could provide a novel, personalized treatment strategy in diabetes mellitus that circumvents the host immune response and the need for direct genetic modification. A medical student involved in this project would have a large role, along with a post-doc, in screening small molecules for their role in increasing enteroendocrine differentiation and increasing beta cell specific targets. This will involve in vitro culturing of human enteroids, isolating RNA and performing qualitative, real-time PCR, and examining protein expression through immunofluorescence. They would also be involved in identifying new small molecules in small-scale, targeted screens and pursuing other cells of interest, including stem cells from the stomach, ileum and colon.