干细胞治疗促进机械牵张诱导的皮肤再生的机制研究

Though skin and soft tissue expansion can harvest extra regenerated skin tissue with normal structure for defect reconstruction, the outcome of the treatment is strictly limited by regeneration capability of the expanded skin, which is a obstacle in promoting its clicical applications. In our previous study, we proved that stem cell transplantation treatment in time can significantly pormote skin regeneration induced by mechanical stretch (Ann Surg. 2011 Jan;253(1):202-9.). This new finding holds great purpose and hope to extend the clinical application of tissue expansion as regenerative medical treatment. Meanwhile, results of our preliminary study demonstrated that key genes represented by HOXA5, et al, play important roles in mechanical stretch induced skin regeneration (Arch Dermatol Res, 2011, 303:125-133), as well as pathways involved SDF-1a (viewed in preliminary results). On the basis of the preliminary study, the purpose of this project is trying to understand the mechanism of mechanical stretch induced skin regeneration with stem cell transplantation using the technique of genomics analysis, the model of in vitro mechanical stretched 3-dimensions organotypic culture system, and the in vivo study of chemokine induced stem cell migration and engraftment, especially focus on the genes of HOXA5 and pathways of SDF-1a, et al. After this study, we hope that the results could help us improve the techniques of skin and soft tissue expansion in repair and reconstructive surgery.

通过对皮肤进行机械牵张，可获得额外的再生组织用于缺损修复，但皮肤有限的再生能力限制了其临床应用潜力。前期研究中，项目组首次证实适时的干细胞移植可显著提升机械牵张下皮肤再生能力（Ann Surg. 2011 Jan;253(1):202-9），这一具重要意义的发现，有望从全新的再生医学角度拓展其临床应用。项目组前期研究初步表明，以HOXA5为代表的相关基因（Arch Dermatol Res, 2011, 303:125-133）和SDF-1a相关的信号通路（见预初研究），在皮肤扩张再生中起重要作用。本项目拟在前期研究基础上，着重就机械牵张下皮肤再生相关基因及信号通路的变化及干细胞治疗的影响路径，特别是以HOXA5等关键基因和SDF-1a信号通路为切入点，进一步通过基因组学、体外三维牵张模型、体内趋化因子干细胞移植转归等的研究，理解干细胞移植促进皮肤机械牵张再生机制，为临床治疗应用提供基础。

通过对皮肤进行机械牵张，可获得再生的皮肤组织用于缺损修复，但皮肤有限的再生能力限制了其临床应用潜力。前期研究中，项目组首次证实适时的干细胞移植可显著提升机械牵张下皮肤再生能力，这一具重要意义的发现，有望从全新的再生医学角度拓展其临床应用。在本项目研究中，完成张力刺激皮肤组织基因芯片检测和生物信息学分析，获得张力启动皮肤再生的关键信号通路，定位促进机械牵张皮肤再生的关键基因CDH1，这一重要发现为临床新药开发提供了基础与方向；明确了张力信号在皮肤细胞中传递机制的研究，并发现长期张力刺激下，Yap靶基因位点甲基化修饰导致皮肤细胞增殖抑制的机制；通过在体示踪模型，完成张力诱导干细胞向皮肤迁移的机制分析，并阐述了干细胞促进张力下皮肤再生的作用机制和转归，明确SDF-1a通路的作用；在此研究基础上，建立了“干细胞介导皮肤牵张再生”技术，开展并完成临床试验一项，验证干细胞移植促进张力下皮肤再生的安全性和有效性，获得一有效的临床获得皮肤组织的再生医学新治疗方法。