title: Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation.
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.
authors.affiliation: 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; Department of Cell Biology, Program in Biological and Biomedical Sciences, Graduate School of Arts and Sciences, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Ivan Achel
authors.initials: IA
authors.lastname: Valdez
authors.affiliation: 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.
authors.forename: Ercument
authors.initials: E
authors.lastname: Dirice
authors.affiliation: 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.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Gupta
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Shirakawa
authors.affiliation: 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; Discovery Research Division, Institute of Molecular and Cell Biology, Proteos, Singapore 138673, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore. Electronic address: ateo@imcb.a-star.edu.sg.
authors.forename: Adrian Kee Keong
authors.initials: AKK
authors.lastname: Teo
authors.affiliation: 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. Electronic address: rohit.kulkarni@joslin.harvard.edu.
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D004703:Endocrine System / Q000166:cytology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010183:Pancreatic Ducts / Q000166:cytology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D007328:Insulin; D009419:Nerve Tissue Proteins; D050796:STAT3 Transcription Factor; C498695:NEUROG3 protein, human; C407737:Neurog3 protein, mouse