Small Molecules Facilitate the Reprogramming of Mouse Fibroblasts into Pancreatic Lineages

Pancreatic beta cells are of great interest for the treatment of type 1 diabetes. A number of strategies already exist for the generation of beta cells, but a general approach for reprogramming nonendodermal cells into beta cells could provide an attractive alternative in a variety of contexts. Here, we describe a step-wise method in which pluripotency reprogramming factors were transiently expressed in fibroblasts in conjunction with a unique combination of soluble molecules to generate definitive endoderm-like cells that did not pass through a pluripotent state. These endoderm-like cells were then directed toward pancreatic lineages using further combinations of small molecules in vitro. The resulting pancreatic progenitor-like cells could mature into cells of all three pancreatic lineages in vivo, including functional, insulin-secreting beta-like cells that help to ameliorate hyperglycemia. Our findings may therefore provide a useful approach for generating large numbers of functional beta cells for disease modeling and, ultimately, cell-based therapy.