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Valdez, Ivan A.

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Valdez

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Ivan A.

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Valdez, Ivan A.

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    The Role of Proinflammatory Cytokines on Pancreatic Cell Plasticity
    (2016-05-05) Valdez, Ivan A.; Blackwell, Keith; Kulkarni, Rohit N.; Tseng, Yu-Hua; Zhou, Qiao; Kim, Jason
    Diabetes mellitus is a complex and heterogeneous group of metabolic diseases characterized by a disruption in blood glucose homeostasis. This could result from an autoimmune destruction of insulin-producing pancreatic beta cells or insulin resistance with subsequent beta cell dysfunction. Thus, a major goal of diabetes research is developing strategies to replenish beta cells. One emerging and promising strategy is harnessing pancreatic plasticity—the ability of pancreatic cells to undergo cellular interconversions— and numerous studies implicate this phenomenon in diverse states of physiological stress or pancreatic injury. In this study, we investigated the effect of inflammatory cytokine stress on the differentiation potential of ductal cells in a human cell line in vitro; on mouse ductal cells by pancreatic intraductal injection in vivo; and throughout the progression of autoimmune diabetes in the non-obese diabetic (NOD) mouse model. We demonstrate 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 cell proliferation as well as ductal-to-endocrine cell reprogramming in vivo independently of hyperglycemic stress. Together, our findings provide novel evidence of inflammatory cytokines in directing ductal- to-endocrine cell differentiation and have significant implications for diabetes and cytokine- driven beta cell regeneration.