iPS-MSCs来源外泌体激活PI3K/Akt通路促进骨再生的作用及机制研究

The treatment of large segment bone defects and bone loss is a clinical thorny problem. Recent studies have demonstrated that stem cell transplantation therapy promotes tissue injury healing mainly through a paracrine mechanism. Current reporting and our previous studies have indicated that exosomes have promise in tissue repair therapy as stem cell transplantation therapy, and the direct treatment with exosomes may overcome the limitations and risks associated with stem cell transplantation therapy, show a broad prospect on clinical application in the future. In consideration of our finding that exosomes derived from iPS-MSCs have obvious effect on promoting bone defects repair, the gene chip analysis suggests that exosomes derived from iPS-MSCs can activate the PI3K/Akt pathway in BMSCs, then we use microRNA array to show that exosomes derived from iPS-MSCs contain microRNAs target PI3K/Akt pathway. We use a series of experiments to clarify the new mechanisms that exosomes derived from iPS-MSCs contains functional microRNAs which can activate PI3K/Akt pathway then promote bone gereneration. The establishment of new technology strategy on taking advantage of stem cell to repair bone defects has significant practical sense.

大段骨缺损及骨丢失的修复一直是临床较为棘手的问题。最新研究显示干细胞的旁分泌机制在其修复组织损伤过程中发挥了重要作用。现有报道及我们的前期研究表明，干细胞分泌的外泌体可发挥类似干细胞样的修复组织损伤的作用，并可避免干细胞直接移植带来的潜在风险，显示出广阔的应用前景。我们在前期研究发现iPS-MSCs来源外泌体可显著修复骨缺损，基因芯片分析提示其可激活BMSCs的PI3K/Akt信号通路，miRNA array分析提示其含有靶向PI3K/Akt通路的关键miRNAs。据此，本课题拟通过系列实验，进一步明确iPS-MSCs来源外泌体促进骨再生的生物学功能，筛选并明确iPS-MSCs来源外泌体中促进骨再生的关键miRNAs及其作用途径，进一步阐明iPS-MSCs来源外泌体通过激活PI3K/Akt信号通路促进骨再生的分子机制。该课题的顺利实施，对于建立应用干细胞修复骨缺损的新技术策略具有重要意义。

干细胞来源的外泌体在修复组织损伤中发挥了重要的作用，其在大段骨缺损及骨丢失的修复中的作用及相关的作用机制尚未阐明。本研究系统的探讨了iPS-MSCs来源外泌体通过PI3K/AKt信号通路促进骨缺损的作用及机制。我们前期研究结果发现iPS-MSCs来源外泌体可显著修复骨缺损，基因芯片分析提示其可激活BMSCs的PI3K/Akt信号通路，miRNA array分析提示其含有靶向PI3K/Akt通路的关键miRNAs。据此，本课题通过系列实验，进一步明确了iPS-MSCs来源外泌体促进骨再生的生物学功能，验证了iPS-MSC-Exos通过激活PI3K/AKt信号通路促进BMSCs成骨分化；我们还发现并证实了iPS-MSC-Exos不仅通过PI3K/AKt信号通路促进成骨发生，同时可激活PI3K/AKt信号通路促进成血管发生，进而促进骨再生。此外，我们发现iPS-MSC-Exos与生物水凝胶具有良好的生物相容性，此生物载体能够促进软骨损伤修复。本课题对于建立应用干细胞修复骨、软骨缺损的新技术策略具有重要意义。