Editors' ChoiceCELL THERAPY

Pancreatic cells play switcheroo

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Science Translational Medicine  15 Jun 2016:
Vol. 8, Issue 343, pp. 343ec97
DOI: 10.1126/scitranslmed.aag1877

Type I diabetes occurs when the insulin-producing β cells of the pancreas are destroyed. To move away from insulin injections, recent research has focused on the development of cell-based therapies for long-term diabetes control, which involves the transfer of insulin-producing stem cells or human cadaver β cells to the diabetic individual. Unfortunately, these therapies can be limited by an eventual immune response, which inactivates the transplanted cells. Using the patient’s own cells would be advantageous.

In a recent study, Koblas and colleagues demonstrated the possibility of rewiring the diabetic patient’s exocrine pancreatic cells, which make up the vast majority of the pancreas and normally produce digestive enzymes. By delivering mRNA encoding three key transcription regulators of β cell differentiation, the authors were indeed able to reprogram these exocrine cells in a dish. In contrast to DNA delivery, the most common method for cell reprogramming, mRNA delivery avoids the potential for insertional mutagenesis and permanent alteration of the genome. The codelivery of synthetic mRNA encoding the proteins PDX1, NGN3, and MAFA coaxed rat pancreatic exocrine cells to produce insulin within 10 days, and induced the expression of genes that maintain proper β cell function. Importantly, reprogrammed insulin-producing cells were responsive to the presence of glucose in the extracellular environment.

This study underscores the potential of reprogramming a diabetic patient’s own pancreatic cells into insulin-producing cells. Future work will evaluate alternative transcription factors that may result in more efficient reprograming, as well as the option to rewire the exocrine cells in vivo—the most likely route to the clinic versus ex vivo manipulation. To achieve in vivo reprogramming, this technology will benefit from a clinically viable delivery vehicle that facilitates high levels of mRNA expression in pancreatic cells.

T. Koblas et al., Reprogramming of pancreatic exocrine cells AR42J into insulin-producing cells using mRNAs for Pdx1, Ngn3, and MafA transcription factors. Mol. Ther. Nucleic Acids 5, e320 (2016). [Full Text]

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