基于皮肤类器官模型探究TGFβ-Collagen-ROCK分子模块调控皮肤及其附属器官再生的机制

由于成体细胞再生能力衰退，皮肤在创伤修复时往往不能再生毛囊等附属器，因而不能形成具备完整功能的皮肤，成为当前世界性科学难题。因此，如何诱导功能性皮肤再生，具有十分重要的科学意义。申请人先前独创类器官培养模型，在体外培养出世界首例皮肤类器官。通过该模型观察到干细胞自组装形成平面皮肤的全过程；将皮肤类器官移植到裸鼠，可新生出含有附属器的完整皮肤。但皮肤类器官形成的具体机制尚未明晰。基于前期研究，我们提出真皮细胞来源的TGFβ-Collagen-ROCK信号在干细胞和成体细胞类器官培养过程中呈现时空表达差异，使干细胞和成体细胞具有不同的自组装和再生能力。本课题将利用前沿科学技术，深入阐明真皮细胞在皮肤类器官形成过程中的细胞学行为，揭示TGFβ-Collagen-ROCK信号调控皮肤类器官形成的分子机制，并以此诱导成体鼠和人类细胞再生皮肤及其附属器，为人类皮肤创伤和脱发等疾病的治疗开拓新思路。

Non-functional scar skin will form if the skin is unable to regenerate appendages such as hair follicles, sweat glands, and sebaceous glands during wound healing. How to induce the regeneration of functional skin is an unsolved scientific problem and has great scientific significance. We previously established a skin organoid culture model, by which we observed that the dissociated stem cells can form planar skin through self-organization, with abundant hair follicles and sebaceous glands formation after transplantation in nude mice. However, the specific cellular and molecular mechanisms of skin organoid formation remain further investigation. Besides, adult mouse and human skin cells lose their ability to self-organize and regenerate. How to improve the regenerative ability of adult cells has become a key issue to be solved urgently in the field of skin regeneration. This project aims to elucidate the cellular and molecular mechanisms of skin organoid formation, to promote adult mouse and human skin cell regeneration. Based on our previous research and recent preliminary data, we propose that dermal cell-derived TGFβ-Collagen-ROCK signals have spatiotemporal expression differences in stem cell and adult cell organoid cultures, leading to their different self-organization and regeneration capabilities. This project will use our established skin organoid culture model and cutting-edge techniques to elucidate the cellular behavior of dermal cells during the self-organization process of skin organoid, and to reveal the molecular mechanism by which the TGFβ-Collagen-ROCK molecular module regulates skin organoid formation. By modulating the TGFβ-Collagen-ROCK molecular molecule, we aim to promote the regenerative ability of adult cells and human cells. We expect that the results of this research will promote the advancement of the basic research of skin and appendages regeneration to the future clinical applications, and to open new therapeutics ideas for wound healing and hair loss-related diseases in human.