M2型巨噬细胞通过旁分泌FGF-2激活毛囊干细胞PI3K/AKT/β-catenin通路参与扩张皮肤再生机制研究

皮肤扩张术是解决大面积皮肤缺损的有效手段。皮肤在扩张过程中受到机械损伤，巨噬细胞会迁移至损伤部位参与坏死组织清除与修复。项目申请人前期首次发现扩张介导的皮肤M2巨噬细胞数量增多，并证实了巨噬细胞是扩张皮肤再生的关键，但M2巨噬细胞参与扩张皮肤再生具体机制仍未阐明。课题组通过转录组测序等方法发现M2巨噬细胞清除可导致扩张皮肤FGF-2表达降低、毛囊干细胞PI3K/AKT/β-catenin通路相关分子表达下降，提示M2巨噬细胞可能通过旁分泌FGF-2激活毛囊干细胞PI3K/AKT通路参与扩张皮肤再生。本课题拟在前期工作基础上，以M2巨噬细胞功能研究为突破口，综合利用局部耗竭、过表达、通路抑制/激活等技术探究M2巨噬细胞调控毛囊干细胞增殖活化的分子机制，阐明FGF-2依赖的PI3K/AKT/β-catenin通路在皮肤扩张过程中的功能和意义，既为扩张皮肤再生提出新的解释，又可发现新的干预靶位。

Tissue expansion is an effective method to treat large skin defects. Skin tissue is damaged under mechanical stretch during tissue expansion and macrophages will migrate into injured site to remove necrotic cells and participate in tissue repair. The applicant of this project found for the first time that the number of M2 macrophages in the expanded skin increased and proved macrophages are necessary for skin regeneration during tissue expansion. However, how M2 macrophages responses in the skin tissue under mechanical stretch is not well characterized during this process. By using transcriptome sequencing, we found FGF-2 and molecules relate to PI3K/AKT/β-catenin pathway in expanded skin reduced after M2 macrophages were depleted, which suggested that M2 macrophages may induce PI3K/AKT/β-catenin-dependent hair follicle stem cell activation and skin regeneration through FGF-2 during tissue expansion. Based on preliminary work, this research plans to use local exhaustion, overexpression and pathway inhibition/activation to elucidate the molecular mechanism of M2 macrophages on regulating the activation of hair follicle stem cells during tissue expansion and clarify the function and significance of the FGF-2-dependent PI3K/AKT/β-catenin pathway during tissue expansion. This study not only provides new explanations for the mechanism of skin regeneration during tissue expansion, but also discovers new intervention targets.