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.
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DOI：
10.1016/j.celrep.2016.03.036
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发表时间：
2016-04-19
期刊：
影响因子：
8.8
通讯作者：
Kulkarni RN
中科院分区：
文献类型：
--
作者：
Valdez IA;Dirice E;Gupta MK;Shirakawa J;Teo AKK;Kulkarni RN
糖尿病研究的一个主要目标是开发补充胰腺产生胰岛素的β细胞的策略。一种新兴的策略是利用胰腺可塑性胰腺细胞进行细胞相互转化的能力这一现象与生理应激和胰腺损伤有关。在这里，我们研究了炎症细胞因子应激对人细胞系中导管细胞分化潜能的影响，通过胰腺导管内注射在小鼠导管细胞中的影响，以及在非肥胖糖尿病（NOD）小鼠模型中自身免疫性糖尿病进展期间的影响。我们发现，炎症细胞因子的侮辱刺激上皮间质转化（EMT）以及内分泌程序在人类胰腺导管细胞通过STAT3依赖性NGN3激活。此外，我们表明，炎症细胞因子激活导管内分泌细胞重编程在体内独立的高血糖应激。总之，我们的研究结果提供了炎症细胞因子指导导管内分泌细胞分化的证据，并对β细胞再生产生影响。
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 investigated 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 independently of hyperglycemic stress. Together, our findings provide evidence that inflammatory cytokines direct ductal-to-endocrine cell differentiation, with implications for beta cell regeneration.