The extracellular matrix (ECM) mechanical properties regulate biological processes, such as fibroblast-myofibroblast transformation (FMT), which is a crucial component in pelvic organ prolapse (POP) development. The ‘Kindlin-2’ protein, expressed by fibroblasts, plays an important role in the development of the mesoderm, which is responsible for connective tissue formation; however, the role of Kindlin-2 in FMT remains to be explored. In this study, we aimed to explore the role of Kindlin-2 in FMT as it relates to POP. We found that ECM stiffness induces autophagy to translocate Kindlin-2 to the cytoplasm of L929 cells, where it interacts with and degrades MOB1, thereby facilitating Yes-associated protein (YAP) entry into the nucleus and influencing FMT progression. Stiffness-induced autophagy was inhibited when using an autophagy inhibitor, which blocked the translocation of Kindlin-2 to the cytoplasm and partially reversed high-stiffness-induced FMT. In patients with POP, we observed an increase in cytoplasmic Kindlin-2 and nuclear YAP levels. Similar changes in vaginal wall-associated proteins were observed in a mouse model of acute vaginal injury. In conclusion, Kindlin-2 is a key gene affecting ECM stiffness, which regulates FMT by inducing autophagy and may influence the development of POP.

中文翻译：

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细胞外基质硬度增加通过诱导自噬介导的 Kindlin-2 细胞质易位调节肌成纤维细胞转化

细胞外基质（ECM）机械特性调节生物过程，例如成纤维细胞-肌成纤维细胞转化（FMT），这是盆腔器官脱垂（POP）发展的关键组成部分。由成纤维细胞表达的“Kindlin-2”蛋白在中胚层的发育中发挥着重要作用，中胚层负责结缔组织的形成；然而，Kindlin-2 在 FMT 中的作用仍有待探讨。在本研究中，我们旨在探讨 Kindlin-2 在 FMT 中与 POP 相关的作用。我们发现 ECM 硬度诱导自噬将 Kindlin-2 易位到 L929 细胞的细胞质，在那里它与 MOB1 相互作用并降解 MOB1，从而促进 Yes 相关蛋白 (YAP) 进入细胞核并影响 FMT 进展。当使用自噬抑制剂时，僵硬诱导的自噬受到抑制，该抑制剂阻止 Kindlin-2 易位到细胞质并部分逆转高硬度诱导的 FMT。在 POP 患者中，我们观察到细胞质 Kindlin-2 和细胞核 YAP 水平增加。在急性阴道损伤的小鼠模型中观察到阴道壁相关蛋白的类似变化。总之，Kindlin-2是影响ECM硬度的关键基因，它通过诱导自噬来调节FMT，并可能影响POP的发生。