外泌体转运microRNA恢复骨质疏松条件下MSCs功能缺陷的机制研究

Previous studies showed that systemic infusion of mesenchymal stem cells (MSCs) generates efficient therapeutic effects on osteoporosis. However, the underlying mechanisms are not fully understood. In our previous study, we found that, in estrogenic deficiency-induced osteoporosis mouse model, donor MSC-secreted exosomes rescued the impaired recipient MSC functions and bone mass. Moreover, the impairment of the recipient MSC functions were highly related to decreases of multiple microRNAs (miRNAs). We also found that exosome could transfer signaling molecules to regulate MSC function. Therefore, we hypothesized that exosome transferred certain miRNA to osteoporotic recipient MSCs and in turn rescued their functions and osteoporotic phenotype. This project will conduct two parts of experimental works to preliminarily explore the mechanisms underlying therapeutic effects generated by exosome, including effects of exosomes on miRNAs expressions of osteoporotic recipient MSCs and transferring of certain miRNA to osteoporotic recipient MSCs. This project represents the hope for exploring mechanisms underlying MSC therapy and provides important experimental and theoretical evidences for MSC therapy applied in osteoporosis.

研究表明间充质干细胞（MSCs）系统移植可以有效治疗骨质疏松，但其机制尚不清楚。我们在前期研究中发现，在雌激素缺乏导致的骨质疏松中，供体MSCs分泌的外泌体能够恢复宿主MSCs的成骨分化功能缺陷，由此逆转骨质疏松的发生；进一步研究显示，骨质疏松宿主MSCs的成骨分化功能缺陷与其多种microRNAs（miRNAs）的异常下调密切相关；我们同时发现，外泌体能够转运关键信号分子调节MSCs功能。由此推测外泌体通过转运特定miRNA至MSCs中恢复其功能并逆转骨质疏松。本研究拟从外泌体对骨质疏松小鼠MSCs中miRNAs表达的影响、外泌体转运特定miRNA至MSCs两方面初步探讨MSCs来源的外泌体逆转骨质疏松的机制。本研究有望揭示MSCs治疗的新机制，为MSCs移植治疗的临床应用提供重要的理论和实验依据。

间充质干细胞（MSCs）系统移植可以有效治疗骨质疏松，但其机制尚不清楚。我们在前期研究中发现，在雌激素缺乏导致的骨质疏松中，供体MSCs分泌的外泌体能够恢复宿主MSCs的成骨分化功能缺陷，由此逆转骨质疏松的发生。该项目拟探讨MSCs释放的外泌体通过转运特定miRNA发挥治疗效果的分子机制。通过该项目为期两年的研究，我们发现移植的供体MSCs分泌的外泌体中含有miR-26a，并能够将其转运至宿主MSCs中，miR-26a进而上调宿主MSCs成骨分化功能、恢复宿主骨量。我们同时发现MSCs移植后会发生显著凋亡，而其在凋亡过程中分泌的细胞囊泡中同样含有miR-26a，并能够恢复骨质疏松宿主MSCs的成骨分化功能及宿主骨量。本项目揭示了MSCs通过分泌外泌体调控宿主细胞功能并发挥疗效的新机制，为MSCs移植治疗的临床应用提供重要的理论和实验依据。