Cdc42在iPS源性的角质形成细胞修复皮肤创伤中的调控机制研究

Skin massive burns often result in open wounds and the treatment of rapid surgical closure with appropriate materials are required . Although the surgical closures with autologous epidermal grafts are effective, they have several disadvantages including donor site morbidity, time constraint, and limited cell yield from primary explanted keratinocytes. Induced pluripotent stem cell (iPSC) could offer the better way to meet the challenge of temporary skin replacement due to their unlimited proliferative capacity, multipotency to differentiate into multiple lineages, importantly and ethical acceptability. Although keratinocytes with the ability to reconstitute epidermal structures can be induced from iPSCs following exposure to retinoic acid and BMP4, the mechanisms controlling their functions in skin wound healing is poorly understood. Clearly, the study to reveal these mechanisms to enhance the clinical application of iPS-derived keratinocytes are required. Recently, we found the skin wound healing delay of the keratinocyte-restricted knockout Cdc42 mice, suggesting a critical role for Cdc42 during keratinocyte mediated skin wound healing. Therefore, we will observe the effect of Cdc42 on the proliferation, migration and differentiation of iPS cells-derived keratinocytes, and explore whether the Wnt/β-catenin and PAK signal pathways is involved or not. We also study the function of Cdc42 in iPS cells-derived keratinocytes mediated skin wound healing in vivo. In our study, we hope to provide basis knowledge for application of iPS cell technology on skin wound repair in the future.

皮肤大面积创伤的临床修复方法目前尚存在着多种缺陷， iPS细胞技术则为其提供了新的治疗途径。目前研究显示iPS细胞源性角质形成细胞的移植治疗能促进小鼠皮肤创伤的修复，但对影响创伤愈合的关键因素-角质形成细胞的功能调控目前尚无报道。本课题组前期研究揭示在角质形成细胞介导的皮肤创伤修复中小G蛋白-Cdc42起到了重要作用，由此，在iPS细胞源性角质形成细胞中Cdc42是否参与了对其功能的调控？是否可以通过调节Cdc42的活性以增强iPS细胞源性角质形成细胞修复皮肤创伤的效果？因此本研究聚焦于探明Cdc42对iPS源性角质形成细胞体外增殖、迁移和分化功能的调控作用，阐明其中Cdc42与 Wnt/β-catenin通路及 PAK信号分子可能的相互信号网络；并进一步体内实验探讨Cdc42对iPS源性角质形成细胞移植治疗皮肤创伤的影响。旨在通过本研究为iPS细胞技术最终能够运用于临床提供理论研究基础。

皮肤大面积创伤的临床修复方法目前尚存在着多种缺陷，iPS细胞技术则为其提供了新的治疗途径。目前研究显示iPS细胞源性角质形成细胞的移植治疗能促进小鼠皮肤创伤的修复，但对影响创伤愈合的关键因素-角质形成细胞的功能调控目前尚无报道。本课题组前期研究揭示在角质形成细胞介导的皮肤创伤修复中小G蛋白-Cdc42起到了重要作用，由此，在iPS细胞源性角质形成细胞中Cdc42是否参与了对其功能的调控？是否可以通过调节Cdc42的活性以增强iPS细胞源性角质形成细胞修复皮肤创伤的效果？因此本研究聚焦于探明Cdc42对iPS源性角质形成细胞体外增殖、迁移和分化功能的调控作用，阐明其中Cdc42与Wnt/β-catenin通路及PAK信号分子可能的相互信号网络；并进一步体内实验探讨Cdc42对iPS源性角质形成细胞移植治疗皮肤创伤的影响。本研究发现Cdc42 促进了 iPS 细胞源性的角质形成细胞的迁移能力，这一现象可能依赖于通过Wnt/β-catenin 通路及 PAK 信号调控；进一步体内实验揭示Cdc42促进了iPS源性的角质形成细胞移植治疗皮肤创伤的作用。本研究为iPS细胞技术最终能够运用于临床提供理论研究基础。