利用跨谱系转化关键因子诱导间充质干细胞分化为汗腺细胞的研究

汗腺再生在皮肤创伤修复和重建过程中的作用至关重要，干细胞为解决汗腺再生的难题提供了新的途径。申请人研究组已证明骨髓来源间充质干细胞（MSC）经体外诱导可分化为具有汗腺细胞表型的细胞。然而，MSC转变为汗腺样细胞的分子机制尚不清楚，从而限制了转化效率的提高。本项目拟采取ChIP-Seq方法筛选汗腺细胞特化的关键转录因子，通过调节这些转录因子和间充质-上皮转化（MET）的信号分子，达到利用其协同作用提高MSC向汗腺细胞特异性重编程的效率，建立稳定的诱导性汗腺细胞生成方案; 进一步通过成熟的体外三维和体内动物模型，评价MSC源性的诱导性汗腺细胞在汗腺再生中的作用。本项目首次从汗腺发育和跨胚层转化机制角度，探索和建立基于细胞重编程和三维微环境的汗腺再生体系，为建立烧创伤后汗腺功能恢复的临床治疗方案提供基础，也为其他复杂组织器官缺损的再生研究提供基于细胞内重编程和细胞外微环境组合模式的策略参考。

Sweat gland regeneration plays the important role in the process of wound repair and remodeling. Stem cells provide a novel approach to resolve this conundrum. Our previous research has proved the possibility that mesenchymal stem cells could acquire phenotype of sweat gland cells after in vitro induction. However, the molecular mechanism of this differentiation remains unclear, limiting the effort to promote the poor differentiation efficiency. Current project is aimed to screen and sort out the key transcription factors for specification of the sweat gland cells by ChIP-Seq technology. Through regulation of these transcription factors and critical signaling molecules involved in mesenchymal-epithelial transition (MET), we will try to enhance the specific reprogramming efficiency of mesenchymal stem cells into sweat gland cells, and to establish the stable production scheme of induced sweat gland cells. In further study, we will evaluate the effects of induced sweat gland cells derived from mesenchymal stem cells on sweat gland regeneration via in vitro 3-D model and in vivo animal model. This will be the first study which stems from the perspective of sweat gland development and mechanism for transition between different germ layers to explore and to establish the system of sweat gland regeneration based on cell reprogramming and 3-D microenvironment, and to provide the foundation of establishing clinical projects of post-traumatic sweat gland function recovery. This study will also offer valuable information for the regeneration of other complex tissues and organs, by application of combined mode-based strategy of intracellular reprogramming events and extracellular microenvironment education.