Generation of Functional Human β Cells in Pigs
Replacement of insulin-producing β cells represents a major goal for the treatment of diabetes. The use of human stem cells to derive functional β cells has shown promise in recent years based on advances in understanding of the genetic and signaling basis of pancreatic organogenesis. However, due to inaccessibility of human tissues at key developmental stages, most of this understanding reflects studies of rodents, whose islet morphology and regulation appear distinct from humans. Such bias in our knowledge underlies the current inability of investigators to direct human stem cell lines into fully functional islet cells. Diabetes research would benefit from studies of islet development in animals more like humans. Here, we propose to investigate pig pancreas and islet development. Pancreas islet physiology in pigs and humans is remarkably similar. Moreover, pig islets are remarkably similar to human islets in size, shape and anatomy. Such resemblance has even supported prior clinical trials to transplant pig islets in human subjects requiring insulin replacement. However, our understanding of porcine pancreatic development is limited at present. Through my proposed research, I will (1) establish genetic approaches to study fetal pig pancreas differentiation, growth and morphogenesis, (2) investigate the molecular mechanisms underlying pig pancreatic islet development, and (3) test if the pig pancreas can be used as a ‘foster organ’ to generate functional insulin-producing human beta cells. We are confident that research proposed here will significantly expand our knowledge of human organ development and advance the development of therapeutic strategies for Type 1 diabetes.