Department of Physiological Chemistry, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8578, Japan.
Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8578, Japan.
Sci Rep. 2017 Apr 21;7:46649. doi: 10.1038/srep46649.
The earlier step of cutaneous wound healing process, re-epithelialization of the wounded skin, is triggered by a variety of growth factors. However, molecular mechanisms through which growth factors trigger skin wound healing are less understood. Here, we demonstrate that hepatocyte growth factor (HGF)/c-Met signaling-induced expression of the small G protein Arf6 mRNA in keratinocytes is essential for the skin wound healing. Arf6 mRNA expression was dramatically induced in keratinocytes at the wounded skin, which was specifically suppressed by the c-Met inhibitor. Wound healing of the skin was significantly delayed in keratinocyte-specific Arf6 conditional knockout mice. Furthermore, Arf6 deletion from keratinocytes remarkably suppressed HGF-stimulated cell migration and peripheral membrane ruffle formation, but did not affect skin morphology and proliferation/differentiation of keratinocytes. These results are consistent with the notion that Arf6 expressed in skin keratinocytes through the HGF/c-Met signaling pathway in response to skin wounding plays an important role in skin wound healing by regulating membrane dynamics-based motogenic cellular function of keratinocytes.
皮肤创伤愈合过程的早期步骤，即受伤皮肤的再上皮化，是由多种生长因子触发的。然而，生长因子触发皮肤创伤愈合的分子机制还不太清楚。在这里，我们证明了肝细胞生长因子 (HGF)/c-Met 信号诱导角质形成细胞中 Arf6 mRNA 的表达对于皮肤创伤愈合是必不可少的。Arf6 mRNA 在受伤皮肤的角质形成细胞中被显著诱导，这一过程可被 c-Met 抑制剂特异性抑制。角质形成细胞特异性 Arf6 条件性敲除小鼠的皮肤创伤愈合明显延迟。此外，从角质形成细胞中删除 Arf6 显著抑制了 HGF 刺激的细胞迁移和外周膜皱褶形成，但不影响角质形成细胞的皮肤形态和增殖/分化。这些结果与以下观点一致，即通过 HGF/c-Met 信号通路在皮肤创伤后在皮肤角质形成细胞中表达的 Arf6 通过调节角质形成细胞的基于膜动力学的运动细胞功能，在皮肤创伤愈合中发挥重要作用。
