Differentiation of Human Embryonic Stem Cells into Pancreatic Endocrine Cells

Abstract

Diabetes is a chronic and debilitating disease that results from insufficient production of insulin from pancreatic β-cells. Islet cell transplantation can effectively treat diabetes, but is currently severely limited by the reliance upon cadaveric donor tissue. Human embryonic stem (ES) cells are a promising alternative source of transplantable insulin-producing β-cells, as they are renewable in vitro and have the inherent capacity to differentiate into pancreatic endocrine cells. Several strategies have been explored for differentiating human ES cells into pancreatic β-cells in vitro, with the most effective to-date being mimicking the key signaling pathways required for pancreas development using small molecules. Although numerous groups have successfully generated insulin-positive cells in vitro using step-wise differentiation protocols, as of yet these cells are not mature pancreatic β-cells as they typically express multiple hormones and are not glucose-responsive. Alternatively, others have transplanted immature pancreatic progenitor cells into immunocompromised animals thus allowing endocrine cell maturation to occur over a prolonged period in vivo. With this strategy functional islet-like endocrine cells have been generated that express key markers of mature pancreatic β-cells, respond to both meal and glucose challenges, and are capable of reversing diabetes in mice. Although there are still numerous challenges to overcome, these studies demonstrate the feasibility of human ES cells as a potential alternative to cadaveric islets for treating patients with diabetes.