Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation
Ivan Achel Valdez,
Ercument Dirice,
Manoj K. Gupta,
Jun Shirakawa,
Adrian Kee Keong Teo,
Rohit N. Kulkarni
Affiliations
Ivan Achel Valdez
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
Ercument Dirice
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
Manoj K. Gupta
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
Jun Shirakawa
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
Adrian Kee Keong Teo
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
Rohit N. Kulkarni
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
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.
