468 Engineering neoislets from islet-derived mesenchymal stem cells
Tuesday November 17, 2015 from 11:00 to 12:30
Room 110

Michael C. Lawrence, United States

Assistant Investigator

Islet Cell Laboratory

Baylor Research Institute


Engineering neoislets from islet-derived mesenchymal stem cells

Prathab Balaji1, Nofit Borenstein-Auerbach1, Mazhar Kanak2, Charles Chang2, Gumpei Yoshimatsu1, Marlon F. Levy3, Bashoo Naziruddin3, Michael C. Lawrence1.

1Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, United States; 2Institute of Biomedical Sciences, Baylor University, Waco, TX, United States; 3Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, United States

Mesenchymal stem cells have been shown to be multipotent in their capacity to differentiate under specifically defined conditions into different cell types, including insulin-producing cells. Here we show that pancreas-derived mesenchymal stem cells can form islet-like structures that secrete insulin in response to glucose (neoislets) that are capable of reversing diabetes in STZ-diabetic mice. Islet-derived mesenchymal stem cells (IMSCs) expressing regulator of G-protein signaling 16 (RGS16) showed the greatest capacity to express both insulin and glucagon. Neoislet differentiation could be rapidly induced within 14 days by small molecules that activated calcinuerin/NFAT and inhibited GSK-3β signaling. Small molecule induction of IMSCs into neoislets correlated with sequential induction of islet differentiation genes neuroD1, Nkx2.2, MafA, and MafB gene expression. NFATc2 activation of NeuroD1 gene promoter in response to small molecule isoxazole-9 induced neoislet programming and bypassed the requirement of Neurogenin 3. Overall, the results indicate that islet-specific RGS16+ adult mesenchymal stem cells are capable of being rapidly induced by small molecules to produce functional neoislets. These findings have potential therapeutic applications for regenerating islets in vivo and/or engineering neoislets in vitro as a source for islet transplantation to prevent or reverse diabetes.

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