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Methods of direct reprogramming: converting pancreatic exocrine cells to beta cells

Scientists in Doug Melton’s laboratory at Harvard University have succeeded in directly reprogramming fully differentiated exocrine cells into beta-cells in adult animals, using a combination of three transcription factors: Ngn3, Pdx1 and Mafa. The induced beta-cells are indistinguishable from endogenous islet beta-cells in morphology and ultrastructure. Also, molecular marker analysis reveals that most of the cells co-express genes essential for beta-cell endocrine function including glucose transporter 2 (Glut2), glucokinase (GCK), prohormone convertase (PC1/3), and the key beta-cell transcription factors NeuroD, Nkx2.2, and Nkx6.1. Importantly, these cells express C-peptide (part of proinsulin) and can synthesize and secrete insulin, reversing hyperglycemia. This direct reprogramming technology holds promise for converting one type of differentiated adult cell into another, and raises the possibility of generating patient-specific and therapeutically important cell types such as pancreatic beta-cells for regenerative medical uses in the future.

Intellectual Property Status: Patent(s) Pending

Applications

In Type I diabetes, insulin-producing beta cells in the pancreas are destroyed by the immune system, leading to hyperglycemia and other complications. The current treatment for Type I diabetes consists of lifelong daily insulin injections; however, in addition to the obvious disadvantages of such a strategy, it is impossible to titrate insulin doses to fluctuating blood glucose levels as precisely as needed, which results in less-than-optimal glucose control. The ideal treatment would be to restore functional beta cells to the pancreas.

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