Small Molecules Facilitate the Reprogramming of Mouse Fibroblasts into Pancreatic Lineages

• Fibroblasts can be directly reprogrammed into definitive endoderm-like cells (DELCs)
• Small molecules can then guide DELCs into pancreatic progenitor-like cells (PPLCs)
• PPLCs give rise to all three pancreatic lineages in vivo
• Functional β-like cells derived from transplanted PPLCs ameliorate hyperglycemia

SummaryPancreatic β cells are of great interest for the treatment of type 1 diabetes. A number of strategies already exist for the generation of β cells, but a general approach for reprogramming nonendodermal cells into β cells could provide an attractive alternative in a variety of contexts. Here, we describe a stepwise 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 β-like cells that help to ameliorate hyperglycemia. Our findings may therefore provide a useful approach for generating large numbers of functional β cells for disease modeling and, ultimately, cell-based therapy.

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