Journal
STEM CELL REPORTS
Volume 12, Issue 2, Pages 351-365Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2018.12.012
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Funding
- NIH [5R01DK114233, 2R25GM103757, 5T32DK108742, 5T32DK007120]
- JDRF Career Development Award [5-CDA-2017-391-A-N]
- Washington University Diabetes Research Center Pilot & Feasibility Award [5P30DK020579]
- Washington University Center of Regenerative Medicine
- Washington University School of Medicine Department of Medicine
- Hope Center Viral Vectors Core at Washington University School of Medicine
- Washington University Diabetes Research Center Imaging Scholarship [5P30DK020579]
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Recent advances in human pluripotent stem cell (hPSC) differentiation protocols have generated insulin-producing cells resembling pancreatic beta cells. While these stem cell-derived beta (SC-beta) cells are capable of undergoing glucose-stimulated insulin secretion (GSIS), insulin secretion per cell remains low compared with islets and cells lack dynamic insulin release. Herein, we report a differentiation strategy focused on modulating transforming growth factor beta (TGF-beta) signaling, controlling cellular cluster size, and using an enriched serum-free media to generate SC-beta cells that express beta cell markers and undergo GSIS with first-and second-phase dynamic insulin secretion. Transplantation of these cells into mice greatly improves glucose tolerance. These results reveal that specific time frames for inhibiting and permitting TGF-beta signaling are required during SC-beta cell differentiation to achieve dynamic function. The capacity of these cells to undergo GSIS with dynamic insulin release makes them a promising cell source for diabetes cellular therapy.
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