Activation of mTORC1 in fibroblasts accelerates wound healing and induces fibrosis in mice
Activation of mTORC1 in fibroblasts accelerates wound healing and induces fibrosis in mice
复制标题
成纤维细胞中 mTORC1 的激活加速伤口愈合并诱导小鼠纤维化
DOI：
10.1111/wrr.12759
复制
发表时间：
2019-09-10
影响因子：
2.9
通讯作者：
Chen, Zhenguo
中科院分区：
文献类型：
--
作者：
Hu, Xiao;Zhang, Hanbin;Chen, Zhenguo
伤口愈合是一个多细胞过程，涉及多种细胞类型的协调努力，包括角质形成细胞、成纤维细胞和内皮细胞。这一过程还受到同样复杂的信号网络的调节，其中涉及多种生长因子、细胞因子和趋化因子。雷帕霉素复合物 1 (mTORC1) 的机制靶点是细胞生长、增殖和分化的中心调节因子。最近的一项研究表明，上皮细胞中 mTORC1 的激活可显着增强上皮细胞的增殖、迁移和皮肤伤口愈合；然而，mTORC1 在伤口愈合过程中成纤维细胞中的作用仍不清楚。在这里，我们通过有条件地删除 mTORC1 抑制剂 TSC1，生成了成纤维细胞中 mTORC1 被激活的基因突变小鼠。成纤维细胞中 mTORC1 的激活显着增加成纤维细胞增殖和收缩性 α-平滑肌肌动蛋白表达，从而促进伤口闭合。 mTORC1 活性升高还会诱导胶原蛋白过度生成，导致过度疤痕和纤维化。重要的是，mTORC1 抑制剂雷帕霉素在很大程度上逆转了加速伤口愈合和纤维化表型。这些观察结果也在原代人真皮成纤维细胞中得到了复制。这些结果共同表明，皮肤成纤维细胞中的 mTORC1 活性是皮肤伤口愈合和疤痕形成的关键协调者。
Wound healing is a multicellular process that involves the coordinated efforts of several cell types, including keratinocytes, fibroblasts, and endothelial cells. This process is also regulated by an equally complex signaling network involving numerous growth factors, cytokines, and chemokines. The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth, proliferation, and differentiation. A recent study showed that mTORC1 activation in epithelial cells dramatically enhanced epithelial cell proliferation, migration, and cutaneous wound healing; however, the roles of mTORC1 in fibroblasts during wound healing remain unknown. Here, we generated genetically mutated mice with activated mTORC1 in fibroblasts by conditionally deleting the mTORC1 inhibitor, TSC1. Activation of mTORC1 in fibroblasts significantly increased fibroblastic cell proliferation and contractile α‐smooth muscle actin expression, thus promoting wound closure. Elevated mTORC1 activity also adversely induced excessive collagen production, leading to excessive scaring and fibrosis. Importantly, both accelerated wound healing and fibrotic phenotypes were largely reversed by the mTORC1 inhibitor, rapamycin. These observations were also replicated in primary human dermal fibroblasts. These results collectively demonstrated that mTORC1 activity in skin fibroblasts was a critical orchestrator in cutaneous wound healing and scarring.