基于iPSCs-NSCs-Exos-piGEL体系诱导神经再生微环境的构建及其对脊髓损伤的修复研究

The treatment of spinal cord injury has been a worldwide problem. The recent development of stem cell technology brought us a new way to repair the injury. Recent studies have demonstrated that stem cell transplantation therapy promotes tissue injury healing mainly through a paracrine mechanism. Transplanting exosomes secreted by stem cells could play a similar role like directly transplanting stem cells. Recently we developed a new phototriggered-imine-crosslink hydrogel, which have an excellent tissue adhesion property. Our preliminary experiment indicated that exosomes derived from iPSC-NSCs have obvious effect on improving functional recovery after spinal cord injury, and the mechanisms may be relative to the protein carried by iPSC-NSC-Exos. We intend to construct a iPSC-NSC-Exos-piGEL, which can adhere to the gap following surgical removal of the thoracic segment of spina cord, to verify the biological functions of promoting the functional recovery after injury and clarify molecular mechanisms of iPSC-NSC-Exos-piGElL in providing excellent neurogenesis-promoting microenvironment, eliciting robust activation of endogenous NSCs and promoting functional recovery. The implementation of this project is of great value for the establishment of a novel strategy for treatment of spinal cord injury.

脊髓损伤的治疗一直是世界性难题，干细胞技术的发展为脊髓损伤等中枢神经系统损伤的修复带来新的契机。最新研究表明旁分泌机制是干细胞发挥其生物学功能的重要方式之一；移植干细胞分泌的外泌体具有类似干细胞样的修复组织损伤的作用。但是，要让外泌体在损伤脊髓局部发挥促修复作用，迫切需要研发一种理想的生物载体。本课题组新研发的光致亚胺交联水凝胶具备优越的组织粘附性能，预实验发现诱导多功能干细胞来源神经干细胞（iPSC-NSCs）分泌的外泌体可明显促进脊髓损伤后神经功能的修复，其机制可能与外泌体内某些关键蛋白因子促进神经再生有关。据此，本课题拟构建能粘附于脊髓缺损组织的iPSC-NSC-Exos-piGEL，体内外实验观察其促进脊髓损伤修复的效果，阐明其改善局部微环境、调控内源性神经干细胞、促进神经再生的具体分子机制。该项目的顺利实施，对于建立应用干细胞修复脊髓损伤等中枢神经系统损伤的新策略具有重要意义。

脊髓损伤的治疗一直是世界性难题，干细胞技术的发展为脊髓损伤等中枢神经系统损伤的修复带来新的契机。最新研究表明旁分泌机制是干细胞发挥其生物学功能的重要方式之一;移植干细胞分泌的外泌体具有类似干细胞样的修复组织损伤的作用。但是，要让外泌体在损伤脊髓局部发挥促修复作用，迫切需要研发一种理想的生物载体。本课题组新研发的光致亚胺交联水凝胶具备优越的组织粘附性能，研究发现诱导多功能干细胞来源神经干细胞(iPSC-NSCs )分泌的外泌体可明显促进脊髓损伤后神经功能的修复。此外，本研究还探索了干细胞源性细胞外囊泡（SC-EVs）对中枢神经系统内神经干细胞衰老情况的调控作用，并阐述了SC-EVs调控巨噬细胞炎性相关基因的重要作用。该研究的成功实施，为干细胞治疗中枢神经系统相关疾病奠定了扎实的基础。