Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
J Nanobiotechnology. 2020 Mar 16;18(1):47. doi: 10.1186/s12951-020-00601-w.
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.
间充质干细胞（MSCs）的移植已被认为是治疗多种疾病（包括骨折）的有效治疗方法。然而，与 MSCs 移植相关的还有一些并发症。有证据表明，MSCs 来源的外泌体（Exos）发挥着类似的旁分泌作用。此外，MSCs 的修复能力会随着年龄的增长而下降。因此，本研究旨在确认来自老年 MSCs 的 Exos 是否会减弱对成骨分化和骨折愈合的保护作用。这项信息被用于探究其潜在的机制。我们成功地从小鼠和老年鼠中分离和鉴定了 MSCs，并获得了 Exos。结果显示，体外 aged-Exos 对 MSCs 成骨分化的作用以及体内骨折愈合的作用明显减弱。通过 miRNA 芯片分析，结果表明 miR-128-3p 在 aged-Exos 中显著上调。体外实验证实 Smad5 是 miR-128-3p 的直接下游靶基因，并被过表达的 miR-128-3p 抑制。一系列的 gain- 和 loss- 功能实验表明，miR-128-3P 在骨折愈合过程中起抑制作用。此外，miR-128-3P 模拟物/抑制剂的作用可以通过应用 Smad5/siSmad5 来逆转。综上所述，这些结果表明，MSCs 衍生的 Exos 的治疗效果可能因 miRNA 的差异表达而有所不同。外泌体 miR-128-3P 拮抗剂可能成为治疗骨折愈合的一种有前途的治疗策略，特别是对老年人。
