PDF(Pubmed)
Abstract：
The pancreatic islet is surrounded by ECM that provides both biochemical and mechanical cues to the islet β-cell to regulate cell survival and insulin secretion. Changes in ECM composition and mechanical properties drive β-cell dysfunction in many pancreatic diseases. While several studies have characterized changes in islet insulin secretion with changes in substrate stiffness, little is known about the mechanotransduction signaling driving altered islet function in response to mechanical cues. We hypothesized that increasing matrix stiffness will lead to insulin secretion dysfunction by opening the mechanosensitive ion channel Piezo1 and disrupting intracellular Ca2+ dynamics in mouse and human islets. To test our hypothesis, mouse and human cadaveric islets were encapsulated in a biomimetic reverse thermal gel (RTG) scaffold with tailorable stiffness that allows formation of islet focal adhesions with the scaffold and activation of Piezo1 in 3D. Our results indicate that increased scaffold stiffness causes insulin secretion dysfunction mediated by increases in Ca2+ influx and altered Ca2+ dynamics via opening of the mechanosensitive Piezo1 channel. Additionally, inhibition of Piezo1 rescued glucose-stimulated insulin secretion (GSIS) in islets in stiff scaffolds. Overall, our results emphasize the role mechanical properties of the islet microenvironment plays in regulating function. It also supports further investigation into the modulation of Piezo1 channel activity to restore islet function in diseases like type 2 diabetes (T2D) and pancreatic cancer where fibrosis of the peri-islet ECM leads to increased tissue stiffness and islet dysfunction.
摘要：
胰岛被ECM包围，ECM为胰岛β细胞提供生化和机械提示，以调节细胞存活和胰岛素分泌。ECM组成和机械特性的变化导致许多胰腺疾病中的β细胞功能障碍。虽然一些研究已经描述了胰岛胰岛素分泌随底物硬度变化的变化，对机械传导信号驱动改变的胰岛功能，以响应机械提示，知之甚少。我们假设增加基质硬度将通过打开机械敏感性离子通道Piezo1并破坏小鼠和人胰岛中的细胞内Ca2动力学而导致胰岛素分泌功能障碍。为了检验我们的假设,将小鼠和人尸体胰岛封装在仿生反向热凝胶（RTG）支架中，该支架具有可调整的刚度，可以与支架形成胰岛斑粘附并在3D中激活Piezo1。我们的结果表明，增加的支架刚度会导致胰岛素分泌功能障碍，这是通过打开机械敏感性Piezo1通道来增加Ca2内流和改变Ca2动力学而介导的。此外,抑制Piezo1挽救了坚硬支架中胰岛中葡萄糖刺激的胰岛素分泌（GSIS）。总的来说,我们的结果强调了胰岛微环境的机械性能在调节功能中的作用。它还支持进一步研究Piezo1通道活性的调节，以恢复2型糖尿病（T2D）和胰腺癌等疾病中的胰岛功能，其中胰岛周围ECM的纤维化导致组织僵硬和胰岛功能障碍增加。
