iPS-MSC来源Exosome促进软骨组织再生修复的分子机理

Until now treatment of articular cartilage injury has remain plagued clinical challenge. The latest research revealed that stem cell transplantation could effectively promote cartilage regeneration. Moreover, exosomes secreted by stem cells were reported to show similar biological function as stem cell transplantation, which brings new opportunity for the treatment of cartilage injury. Our previous studies showed that exosomes derived from iPS-MSCs (iPS-MSC-Exos) could be absorbed by chondrocytes and significantly promote cartilage tissue repair. Gene chip analysis showed that iPS-MSC-Exos contained a variety of microRNAs which is closely related to articular cartilage injury. Combined with recent reports that microRNAs play important role in cartilage regeneration and tissue repair, we speculate that iPS-MSC-Exos can promote cartilage regeneration through carrying specific miRNAs to regulate downstream target genes. Accordingly, our project plans to evaluate the cartilage repairing effects of iPS-MSC-Exos through series of experiments, and identify key microRNAs and related molecular pathway resposibe for the biological function. Based on the research, we are going to give an preliminary explantation for the molecular mechanism that iPS-MSC-Exos promote cartilage regeneration. This will provide scientific theoretical foundation to utilize stem cell for research and development of new technology for the clinical treatment of osteoarthritis and other cartilage injuries.

关节软骨损伤的治疗一直是困扰临床的难题。最新研究表明干细胞移植可有效修复软骨损伤，且干细胞分泌的外泌体（Exosome）具有类似干细胞样的功能，从而为软骨损伤的治疗研究带来新的契机。我们的前期研究发现iPS-MSC分泌的Exosome（iPS-MSC-Exos）可被软骨细胞摄取并显著促进损伤软骨的修复，芯片检测显示iPS-MSC-Exos中含有多种与软骨再生相关miRNAs。结合miRNAs在软骨损伤修复中发挥重要作用的相关报道，我们推测iPS-MSC-Exos可能是通过其携带的某些特异miRNAs调控下游靶基因促进软骨的再生与修复。据此，本课题拟通过系列实验客观评估iPS-MSC-Exos促进软骨再生的功能，明确iPS-MSC-Exos中促进软骨再生的关键miRNAs及其分子途径，阐明iPS-MSC-Exos促进软骨再生的分子机理，为利用干细胞技术治疗软骨损伤性疾病研发新技术提供依据。

由于关节软骨的再生能力有限，软骨损伤的治疗一直是临床上非常棘手的难题。我们的前期研究表明诱导多能干细胞分化形成的间充质干细胞来源的小细胞外囊泡（iPS-MSC-sEVs）具有强大的促进组织修复再生的作用。而iPS-MSC-sEVs对于软骨损伤是否同样具有良好的修复作用及其作用机制值得深入研究。本实验通过构建软骨缺损和骨关节炎两种模型，评价了iPS-MSC-sEVs对于损伤软骨的修复作用。结果表明iPS-MSC-sEVs具有显著的促软骨再生作用。此外，为使iPS-MSC-sEVs在软骨损伤部位持续性发挥修复作用，我们构建了光敏水凝胶负载iPS-MSC-sEVs的复合型生物材料，结果表明其具有持续的促软骨再生功能。我们还探索性地比较了iPS-MSC-sEVs和滑膜间充质干细胞分泌的sEVs（SMMSC-sEVs）对骨关节炎模型小鼠软骨的修复功能，结果发现iPS-MSC-sEVs修复功能明显强于SMMSC-sEVs。该结果提示干细胞来源sEVs的软骨修复功能可能与干细胞本身的分化程度密切相关。因此，我们进一步探索了胚胎干细胞来源的sEVs（ESC-sEVs）对骨关节炎关节软骨的修复作用及其机制，结果表明ESC-sEVs可能是通过调控FOXO4诱导衰老软骨细胞凋亡的途径发挥软骨保护作用，延缓骨关节炎进展。本课题为利用干细胞治疗软骨损伤的技术提供了坚实的理论基础，对干细胞再生医学技术的临床转化具有重要现实意义。