脂肪源基质水凝胶诱导ADSCs成脂分化：创伤性毛囊新生的新策略

Wound related hair follicle regeneration can promote skin wound healing. Intradermal adipocyte is the essential component for hair follicle stem cells (HFSCs) microenvironment. Our previous experiments have proved that, hydrogel from acellular porcine adipose tissue (HAPA) can induce adipogenic differentiation of multiple mesenchymal stem cells and induce homing of endogenous stem cells. Furthermore, adding ADSCs in HAPA can promote skin wound healing and the newly formed skin was more close to normal skin. BMP/PPARγ signaling pathways plays an important role in inducing mesenchymal stem cell differentiation and hair follicle activation. Therefore, the study is designed to test the hypothesis that, HAPA can promote wound related hair follicle regeneration and wound healing via inducing ADSCs adipogenic differentiation. To prove the hypothesis, HAPA and ADSCs will be applied to skin wound of mice, and the activation of surrounding HFSCs, hair follicle regeneration and wound healing will be detected. Furthermore, the regulation mechanism of BMP/PPARγ will be explored. Taken together, the study might provide a novel insight for the mechanism of adipocyte induced hair follicle regeneration and provide new therapeutic targets for the treatment skin wound healing.

毛囊新生是皮肤创伤功能性修复的关键之一。皮内脂肪细胞是毛囊干细胞（HFSCs）微环境重要的组分，我们在前期实验中已证实脂肪源基质水凝胶具有成脂诱导特性及促进内源性干细胞归巢特性，可显著促进创面脂肪细胞新生及创伤性毛囊再生，且新生皮肤结构更接近正常皮肤。BMP/PPARγ可通过介导干细胞成脂分化及HFSCs稳态参与调控毛囊周期。在本项目中我们提出“脂肪源基质水凝胶诱导ADSCs成脂分化可促进创伤性毛囊再生及皮肤缺损功能性修复”的假设。为此，本项目拟以脂肪微环境为研究对象，从细胞、器官及整体动物三个层面研究脂肪源基质水凝胶诱导新生的皮内脂肪细胞对创周HFSCs活化、创面毛囊新生及新生皮肤结构的影响，并通过转录组测序等技术探索BMP/PPARγ信号通路在脂肪介导的毛囊新生过程中的交互调控机制，进一步丰富和完善皮肤创伤修复的机制理论，为皮肤创伤治疗提供全新的观点。

由各种创伤及疾病导致的皮肤创伤是常见的临床问题。理想的皮肤创伤修复要求皮肤结构和功能重建。模拟组织器官生理微环境是实现再生的重要思路。脂肪细胞及其微环境在皮肤发育及创面愈合扮演的角色近年来受到学术领域关注。在前期研究中我们发现脂肪源基质水凝胶可通过诱导干细胞归巢及分化等关键生物进程为局部提供脂肪新生微环境，有利于皮肤功能性创伤修复。本研究在此基础上深入探讨其内在机制，基于质谱的蛋白组学分析发现HAPA显著相关的生物学进程包括多个皮肤相关事件，证实HAPA可通过促进巨噬细胞M2型极化实现局部免疫调节作用（上调IL-10，下调IL-1β、LI-6、TNFα），有助于提高成血管相关生长因子（VEGF、bFGF、PDGF）旁分泌作用，介导血管新生和上皮细胞爬行,为创面愈合提供直接封闭作用。同时，HAPA在低氧环境下保持原有成脂诱导特性，减少移植ADSCs及游离脂肪组织凋亡，可作为HAPA辅助游离脂肪移植的辅助剂，在软组织填充层面进一步提高皮肤全层缺损修复。该研究从脂肪微环境角度为皮肤创面愈合提供一种新策略，对进一步研究脂肪源基质来源的生物支架材料具有重要意义。