Exosomal miRNA-128-3p from mesenchymal stem cells of aged rats regulates osteogenesis and bone fracture healing by targeting Smad5
Exosomal miRNA-128-3p from mesenchymal stem cells of aged rats regulates osteogenesis and bone fracture healing by targeting Smad5
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来自老年大鼠间充质干细胞的外泌体 miRNA-128-3p 通过靶向 Smad5 调节成骨和骨折愈合
DOI：
10.1186/s12951-020-00601-w
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发表时间：
2020-03-16
影响因子：
10.2
通讯作者：
Yin, Guoyong
中科院分区：
文献类型：
--
作者：
Xu, Tao;Luo, Yongjun;Yin, Guoyong
骨髓间充质干细胞（MSCs）移植已被认为是一种有效的治疗包括骨折的各种疾病的治疗方法。然而，有相关的并发症沿着与骨髓间充质干细胞移植。有证据表明来源于MSC的外泌体（exosomes，Exos）发挥类似的旁分泌功能。此外，MSC的修复能力随着年龄的增长而下降。因此，本研究旨在确认Exos对老化MSCs的成骨分化和骨折愈合的保护功能是否减弱。这些信息用于研究潜在的机制。成功地从青年和老年大鼠中分离和鉴定了MSC，并获得了Exos。体外实验表明，hexod-Exos对MSCs的成骨分化和骨折愈合有明显的抑制作用。使用miRNA阵列分析，显示miR-128- 3 p在pMD-Exos中显著上调。体外实验证实Smad 5是miR-128- 3 p的直接下游靶点，并被过表达的miR-128- 3 p抑制。一系列功能获得和丧失实验表明，miR-128- 3 P在骨折愈合过程中起抑制作用。此外，miR-128- 3 P模拟物/抑制剂引起的作用通过Smad 5/siSmad 5的应用而逆转。综上所述，这些结果表明，MSC衍生的Exos的治疗效果可能根据miRNA的差异表达而变化。外泌体miR-128- 3 P可能作为骨折愈合的有希望的治疗策略，特别是对于老年人。
Transplantation of mesenchymal stem cells (MSCs) has been considered an effective therapeutic treatment for a variety of diseases including bone fracture. However, there are associated complications along with MSCs transplantation. There is evidence to show that exosomes (Exos) derived from MSCs exert a similar paracrine function. In addition, repair capabilities of MSCs decline with age. Hence, this study aims to confirm whether the Exos protective function on osteogenic differentiation and fracture healing from aged MSCs was attenuated. This information was used in order to investigate the underlying mechanism. MSCs were successfully isolated and identified from young and aged rats, and Exos were then obtained. Aged-Exos exhibited significantly attenuated effects on MSCs osteogenic differentiation in vitro and facture healing in vivo. Using miRNA array analysis, it was shown that miR-128-3p was markedly upregulated in Aged-Exos. In vitro experiments confirmed that Smad5 is a direct downstream target of miR-128-3p, and was inhibited by overexpressed miR-128-3p. A series gain- and loss- function experiment indicated that miR-128-3P serves a suppressor role in the process of fracture healing. Furthermore, effects caused by miR-128-3P mimic/inhibitor were reversed by the application of Smad5/siSmad5. Taken together, these results suggest that the therapeutic effects of MSCs-derived Exos may vary according to differential expression of miRNAs. Exosomal miR-128-3P antagomir may act as a promising therapeutic strategy for bone fracture healing, especially for the elderly.