利用3D微环境与组蛋白修饰机制调控间充质干细胞修复难愈性创面的研究

皮肤难愈性创面以其趋高的发病率和难治性成为当今危害人类健康的重要疾病类型。具有促进创面愈合和多种组织器官再生功能的间充质干细胞（MSC）有望成为其新型治疗手段。然而申请人前期研究发现，相比于正常创面，MSC在难愈性创面中的促愈功能下降，说明微环境中存在对外源性MSC的抑制因素，但其分子机制尚不清楚。本项目拟建立影响MSC的三维创面微环境模型，于转录组水平研究细胞生物学行为受微环境影响的变化规律和关键分子，重点阐述组蛋白甲基化修饰模式及其控制因素在微环境导致基因表达变化中的调控作用，深入了解染色质结构变化对细胞功能的决定机制，发展可有效调节胞外创伤微环境和核内表观遗传修饰的3D微环境构建技术，评价3D-MSC/微载体复合体在成熟的皮肤难愈性创面动物模型中的再生修复作用。本项目的开展不仅能在表观遗传学水平深入理解细胞功能的调控机制，而且能为建立基于MSC的难愈性创面新型治疗方案奠定基础。

Non-healing cutaneous wound has become a common and dangerous disease with its rising tendency of incidence. Therapeutic application of mesenchymal stem cells (MSC) is promising since they have been proved to be able to promote cutaneous wound healing and the regeneration of multiple tissues and organs. However, our previous research found that MSC exhibit inferior function in the non-healing cutaneous wound compared to those under normal condition. This indicates the existence of inhibitory factors and cascades within the complex healing system, but the mechanism underlying this remains exclusive. The current project will establish multiple traumatic culture models which simulate the 3D microenvironment at the wound site, and elucidate the dynamic change and critical molecules which mediate the effect of environmental stimuli on the MSC. Experimental design will be aimed to figure out how the modification pattern of histone methylation and their regulation control the gene expression in the MSC, and to find the link between this level of control and cell function. Based on our established systems, we will explore the treatment of the non-healing cutaneous wound on the animal model by using 3D bioprinted MSC/microcarrier complex which combine the regulative effect of external microenvironment and internal epigenetic modification. The current project could not only deepen our understanding of the mechanism underlying the regulation of reparative cell function at the epigenetic level, but also lay the foundation for the future establishment of MSC-based therapy for the non-healing cutaneous wound.