Epidermal growth factor induces adult human islet cell dedifferentiation
Epidermal growth factor induces adult human islet cell dedifferentiation
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DOI：
10.1530/joe-11-0213
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发表时间：
2011-12-01
影响因子：
4
通讯作者：
Rosenberg, Lawrence
中科院分区：
文献类型：
--
作者：
Hanley, Stephen C.;Assouline-Thomas, Beatrice;Rosenberg, Lawrence
鉴于成人胰岛的形态发生可塑性的固有治疗潜力，控制其细胞分化的因素的鉴定是令人感兴趣的。表皮生长因子（EGF）家族以前已在胰腺器官发生的背景下确定。我们研究了EGF在体外模型中的作用，即成人胰岛嵌入胶原凝胶中并去分化成导管样上皮结构（DLS）。我们证明，DLS的形成是EGF依赖性的，而残留的DLS的形成在没有添加EGF的情况下被废除EGF受体抑制剂治疗。在信号传导方面，EGF给药导致DLS形成早期c-Jun NH 2-末端激酶（JNK）磷酸化增加，DLS形成过程晚期AKT和细胞外信号调节激酶（ERK）磷酸化增加，同时去分化细胞增殖增加。在没有EGF的情况下，没有看到这些磷酸化变化，并且在培养10天后看到的DLS上皮细胞增殖的典型增加减弱。因此，在我们的模型中，EGF是胰岛细胞去分化所必需的，在DLS形成的开始（通过JNK）和这些去分化细胞的增殖（通过AKT和ERK）中起着重要作用。内分泌学杂志（2011）211，231-239
Given the inherent therapeutic potential of the morphogenetic plasticity of adult human islets, the identification of factors controlling their cellular differentiation is of interest. The epidermal growth factor (EGF) family has been identified previously in the context of pancreatic organogenesis. We examined the role of EGF in an in vitro model whereby adult human islets are embedded in a collagen gel and dedifferentiated into duct-like epithelial structures (DLS). We demonstrated that DLS formation was EGF dependent, while residual DLS formation in the absence of added EGF was abrogated by EGF receptor inhibitor treatment. With respect to signaling, EGF administration led to an increase in c-Jun NH2-terminal kinase (JNK) phosphorylation early in DLS formation and in AKT and extracellular signal-regulated kinase (ERK) phosphorylation late in the process of DLS formation, concomitant with the increased proliferation of dedifferentiated cells. In the absence of EGF, these phosphorylation changes are not seen and the typical increase in DLS epithelial cell proliferation seen after 10 days in culture is attenuated. Thus, in our model, EGF is necessary for islet cell dedifferentiation, playing an important role in both the onset of DLS formation (through JNK) and in the proliferation of these dedifferentiated cells (through AKT and ERK). Journal of Endocrinology (2011) 211, 231-239