Fang Shuo, Xu Chen, Zhang Yuntong, Xue Chunyu, Yang Chao, Bi Hongda, Qian Xijing, Wu Minjuan, Ji Kaihong, Zhao Yunpeng, Wang Yue, Liu Houqi, Xing Xin
Department of Plastic and Reconstruction, Shanghai Changhai Hospital Affiliated to Second Military Medical University, Shanghai, People's Republic of China.
Department of Spinal Surgery, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, People's Republic of China.
Stem Cells Transl Med. 2016 Oct;5(10):1425-1439. doi: 10.5966/sctm.2015-0367. Epub 2016 Jul 7.
: Excessive scar formation caused by myofibroblast aggregations is of great clinical importance during skin wound healing. Studies have shown that mesenchymal stem cells (MSCs) can promote skin regeneration, but whether MSCs contribute to scar formation remains undefined. We found that umbilical cord-derived MSCs (uMSCs) reduced scar formation and myofibroblast accumulation in a skin-defect mouse model. We found that these functions were mainly dependent on uMSC-derived exosomes (uMSC-Exos) and especially exosomal microRNAs. Through high-throughput RNA sequencing and functional analysis, we demonstrated that a group of uMSC-Exos enriched in specific microRNAs (miR-21, -23a, -125b, and -145) played key roles in suppressing myofibroblast formation by inhibiting the transforming growth factor-β2/SMAD2 pathway. Finally, using the strategy we established to block miRNAs inside the exosomes, we showed that these specific exosomal miRNAs were essential for the myofibroblast-suppressing and anti-scarring functions of uMSCs both in vitro and in vivo. Our study revealed a novel role of exosomal miRNAs in uMSC-mediated therapy, suggesting that the clinical application of uMSC-derived exosomes might represent a strategy to prevent scar formation during wound healing.
Exosomes have been identified as a new type of major paracrine factor released by umbilical cord-derived mesenchymal stem cells (uMSCs). They have been reported to be an important mediator of cell-to-cell communication. However, it is still unclear precisely which molecule or group of molecules carried within MSC-derived exosomes can mediate myofibroblast functions, especially in the process of wound repair. The present study explored the functional roles of uMSC-exosomal microRNAs in the process of myofibroblast formation, which can cause excessive scarring. This is an unreported function of uMSC exosomes. Also, for the first time, the uMSC-exosomal microRNAs were examined by high-throughput sequencing, with a group of specific microRNAs (miR-21, miR-23a, miR-125b, and miR-145) found to play key roles in suppressing myofibroblast formation by inhibiting excess α-smooth muscle actin and collagen deposition associated with activity of the transforming growth factor-β/SMAD2 signaling pathway.
在皮肤伤口愈合过程中，肌成纤维细胞聚集导致的过度瘢痕形成具有重要的临床意义。研究表明，间充质干细胞（MSCs）可促进皮肤再生，但MSCs是否会促进瘢痕形成仍不明确。我们发现，脐带间充质干细胞（uMSCs）可减少皮肤缺损小鼠模型中的瘢痕形成和肌成纤维细胞积累。我们发现这些功能主要依赖于uMSC衍生的外泌体（uMSC-Exos），尤其是外泌体中的微小RNA。通过高通量RNA测序和功能分析，我们证明了一组富含特定微小RNA（miR-21、-23a、-125b和-145）的uMSC-Exos通过抑制转化生长因子-β2/SMAD2途径在抑制肌成纤维细胞形成中起关键作用。最后，使用我们建立的阻断外泌体内微小RNA的策略，我们表明这些特定的外泌体微小RNA对于uMSCs在体外和体内抑制肌成纤维细胞及抗瘢痕形成的功能至关重要。我们的研究揭示了外泌体微小RNA在uMSC介导的治疗中的新作用，表明uMSC衍生外泌体的临床应用可能是一种预防伤口愈合过程中瘢痕形成的策略。
外泌体已被确定为脐带间充质干细胞（uMSCs）释放的一种新型主要旁分泌因子。据报道，它们是细胞间通讯的重要介质。然而，仍不清楚MSCs衍生外泌体内携带的究竟是哪种分子或分子组能够介导肌成纤维细胞功能，尤其是在伤口修复过程中。本研究探讨了uMSC外泌体微小RNA在肌成纤维细胞形成过程中的功能作用，肌成纤维细胞形成可导致过度瘢痕形成。这是uMSC外泌体一项未被报道的功能。此外，首次通过高通量测序检测uMSC外泌体微小RNA，发现一组特定的微小RNA（miR-21、miR-23a、miR-125b和miR-145）通过抑制与转化生长因子-β/SMAD2信号通路活性相关的过量α-平滑肌肌动蛋白和胶原蛋白沉积在抑制肌成纤维细胞形成中起关键作用。
