Department of Surgery, McGill University, Montreal, Quebec, Canada.
J Endocrinol. 2011 Dec;211(3):231-9. doi: 10.1530/JOE-11-0213. Epub 2011 Sep 20.
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).
鉴于成人胰岛的形态发生可塑性具有潜在的治疗作用，因此鉴定控制其细胞分化的因素具有重要意义。表皮生长因子（EGF）家族先前已在胰腺器官发生的背景下被鉴定出来。我们在体外模型中研究了 EGF 的作用，在此模型中，成年胰岛被嵌入胶原凝胶中，并向导管样上皮结构（DLS）去分化。我们证明 DLS 的形成依赖于 EGF，而在没有添加 EGF 的情况下，残留的 DLS 形成被 EGF 受体抑制剂处理所阻断。就信号转导而言，EGF 给药导致 DLS 形成早期 c-Jun NH2-末端激酶（JNK）磷酸化增加，以及 DLS 形成后期 AKT 和细胞外信号调节激酶（ERK）磷酸化增加，同时伴随着去分化细胞的增殖增加。在没有 EGF 的情况下，不会出现这些磷酸化变化，并且在培养 10 天后观察到的 DLS 上皮细胞增殖的典型增加被减弱。因此，在我们的模型中，EGF 对于胰岛细胞去分化是必需的，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）中都发挥着重要作用。
