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  current news   Press   selected story    
     
  9 May 2016  
 
Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation
 
 




Authors
Ivan Achel Valdez1,2, Ercument Dirice1, Manoj K. Gupta1, Jun Shirakawa1, Adrian Kee Keong Teo1,3,4,5,6,7,* and Rohit N. Kulkarni1,7,*

1 Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center and Department of Medicine,   Brigham and Women’s Hospital, Harvard Stem Cell Institute and Harvard Medical School, Boston, MA   02215, USA
2
 Department of Cell Biology, Program in Biological and Biomedical Sciences, Graduate School of Arts and Sciences, Harvard University, Cambridge, MA 02138, USA
3 Discovery Research Division, Institute of Molecular and Cell Biology, Proteos, Singapore 138673,   Singapore
4 School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
5
 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore,   Singapore 117596, Singapore
6
 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
7 Co-senior author

* Correspondence: ateo@imcb.a-star.edu.sg (A.K.K.T.), rohit.kulkarni@joslin.harvard.edu (R.N.K.)

Published in Cell Reports on 19th April 2016

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 nonobese diabetic (NOD) mouse model. We find that inflammatory cytokine insults stimulate epithelialto- 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.

Graphical abstract::


Figure Legend:
Proinflammatory cytokines induce STAT3-dependent NGN3 activation and endocrine differentiation. Inflammatory cytokine stress induces epithelial-to-mesenchymal transition (EMT) in human pancreatic ductal cells as well as STAT3-dependent NGN3 activation in vitro. Inflammatory cytokines also activate endocrine reprogramming in mouse ductal cells in vivo independently of hyperglycemic stress.

For more information on Adrian TEO's laboratory, please click here.