Journal
CELL REPORTS
Volume 15, Issue 3, Pages 460-470Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.03.036
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Funding
- NIH [F31DK098931, P01 DK036836, R01 DK67536, R01 DK103215, R01 DK055523]
- Juvenile Diabetes Research Foundation [3APF-2014-220-A-N, 3-2013-236]
- Institute of Molecular and Cell Biology, A*STAR, NHG-KTPH [SIG/14033]
- NUHS-CG Metabolic In-Vitro Core Seed
- JCO Career Development Award, A*STAR [15302FG148]
- Harvard Stem Cell Institute [SG-0078-12-00]
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A major goal of diabetes research is to develop strategies that replenish pancreatic insulin-producing beta cells. One emerging strategy is to harness pancreatic plasticity-the ability of pancreatic cells to undergo cellular interconversions-a phenomenon implicated in physiological stress and pancreatic injury. Here, we investigate the effects of inflammatory cytokine stress on the differentiation potential of ductal cells in a human cell line, in mouse ductal cells by pancreatic intraductal injection, and during the progression of autoimmune diabetes in the non-obese diabetic (NOD) mouse model. We find that inflammatory cytokine insults stimulate epithelial-to-mesenchymal transition (EMT) as well as the endocrine program in human pancreatic ductal cells via STAT3-dependent NGN3 activation. Furthermore, we show that inflammatory cytokines activate ductal-to-endocrine cell reprogramming in vivo independent of hyperglycemic stress. Together, our findings provide evidence that inflammatory cytokines direct ductal-to-endocrine cell differentiation, with implications for beta cell regeneration.
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