Mechanisms to generate functional replacement β-cells from multipotent human stem cells
Replacement of tissues and organs with multipotent stem cell sources has been the focus of intensive investigations. Absolute or relative deficiency of insulin-producing pancreatic β-cells underlies both type 1 and type 2 diabetes mellitus. Despite considerable recent progress, many fundamental issues related to the specialization and functional maturation of replacement β-cells from sources like human embryonic stem cells or induced pluripotent stem cells remain to be resolved. Our goal is to exploit novel mechanisms and pathways, discovered through our prior studies of native mouse and human β-cell development, to drive maturation of functional replacement β-cells produced from cultured human ES and iPS cells.
Our proposals aims are: (1) Identify endogenous signaling pathways that stimulate functional maturation of Insulin-secreting cells produced from human ES or iPS cells. (2) Identify small molecules through candidate screens that control and enhance β-cell maturation. (3) Use new chemical-genetic methods to stimulate electrical activity and provoke maturation of Insulin-secreting cells.
Successful completion of milestones in our proposal should accelerate attainment of our goal to produce functional replacement β-cells from human ES and iPS cells that are indistinguishable from native pancreatic islet β-cells.
Diabetes mellitus is a terrible disease afflicting millions worldwide, including citizens of California. Our studies address a root cause of the major forms of diabetes and propose to generate strategies to regenerate or replace pancreatic beta-cells, the source of the hormone insulin which is deficient in diabetes. Our studies target cell pathways and molecular mechanisms discovered from prior studies by our laboratory. These pathways and mechanisms regulate growth, development and maturation of many vital organs, including the heart, brain, bone, and pancreas. Thus, results and experience gained from completion of studies proposed here could greatly accelerate progress in generating replacement cells for multiple tissues and organs relevant to the CIRM mission.