Proinflammatory cytokines induce endocrine differentiation in pancreatic ductal cells via STAT3-dependent NGN3 activation

Proinflammatory cytokines induce endocrine differentiation in pancreatic ductal cells via STAT3-dependent NGN3 activation
Title:
Proinflammatory cytokines induce endocrine differentiation in pancreatic ductal cells via STAT3-dependent NGN3 activation
Other Titles:
Cell Reports
Keywords:
Publication Date:
07 April 2016
Citation:
Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation Valdez, Ivan Achel et al. Cell Reports, Volume 15, Issue 3, 460 - 470
Abstract:
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.
License type:
http://creativecommons.org/licenses/by-nc-nd/4.0/
Funding Info:
We are grateful to Dr. Susan Bonner-Weir and Brooke Sullivan for kindly providing an aliquot of the Ngn3 antibody and advice and assistance with immunostaining protocols. I.A.V. is supported by an NIH F31DK098931 award. E.D. was supported by the Juvenile Diabetes Research Foundation postdoctoral fellowship 3APF-2014-220-A-N. A.K.K.T. was supported by the Juvenile Diabetes Research Foundation postdoctoral fellowship 3-2013-236 and is currently supported by the Institute of Molecular and Cell Biology, A*STAR, NHG-KTPH SIG/14033, the NUHS-CG Metabolic In-Vitro Core Seed Funding, and JCO Career Development Award 15302FG148, A*STAR. R.N.K. is supported by Harvard Stem Cell Institute Award SG-0078-12-00 and NIH grants P01 DK036836, R01 DK67536, R01 DK103215, and R01 DK055523.
Description:
ISSN:
2211-1247
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