Antifibrotic effects and mechanisms of mesenchymal stem cell-derived exosomes in a systemic sclerosis mouse model: Possible contribution of miR-196b-5p
Antifibrotic effects and mechanisms of mesenchymal stem cell-derived exosomes in a systemic sclerosis mouse model: Possible contribution of miR-196b-5p
复制标题
DOI：
10.1016/j.jdermsci.2021.08.006
复制
发表时间：
2021-11-02
影响因子：
4.6
通讯作者：
Motegi, Sei-ichiro
中科院分区：
文献类型：
--
作者：
Baral, Hritu;Uchiyama, Akihiko;Motegi, Sei-ichiro
背景：系统性硬化症（SSc）是一种结缔组织疾病，其特征是皮肤和内脏器官发生纤维化。越来越多的证据表明间充质干细胞（MSC）可用于治疗纤维化疾病。最近的研究表明，间充质干细胞的一些生物学效应是由于外泌体的分泌所致。然而，间充质干细胞衍生的外泌体在皮肤纤维化中的确切机制尚不清楚。目的：我们旨在阐明间充质干细胞衍生的外泌体对 SSc 皮肤纤维化的影响及其抑制纤维化作用的机制。方法：采用超速离心法从MSCs中收集外泌体。我们研究了 MSC 衍生的外泌体对博莱霉素诱导的 SSc 小鼠模型皮肤纤维化的抑制作用。收集注射部位的皮肤样本进行进一步检查，并对 MSC 衍生的外泌体进行 micro-RNA 分析。结果：注射间充质干细胞衍生的外泌体可显着抑制博莱霉素诱导的小鼠真皮纤维化。间充质干细胞衍生的外泌体显着减少了病变皮肤中胶原蛋白的量以及α-SMA+肌成纤维细胞和CD68+巨噬细胞的数量。他们还在体外降低了成纤维细胞中 I 型胶原和 TGF-β 受体 1 的表达。此外，micro-RNA 分析表明，MSC 衍生的外泌体中的几种 microRNA 具有抗纤维化潜力。我们证实，成纤维细胞中 miR-196b-5p 的过度表达显着抑制 I 型胶原 α2 的表达。结论：本研究表明，外泌体中 miR-196b-5p 抑制 I 型胶原表达可能是 MSC 抑制 SSc 小鼠模型皮肤纤维化的机制之一。 (c) 2021 年日本皮肤病研究学会。由 Elsevier B.V. 出版。保留所有权利。
Background: Systemic sclerosis (SSc) is a connective tissue disorder characterized by the development of fibrosis in the skin and internal organs. Increasing evidence suggests that mesenchymal stem cells (MSCs) can be used to a treatment for fibrotic diseases. Recent studies have demonstrated that some of the biological effects of MSCs are due to the secretion of exosomes. However, the precise mechanisms underlying MSCs-derived exosomes in skin fibrosis are not well understood. Objective: We aimed to elucidate the effect of MSCs-derived exosomes on skin fibrosis in SSc and the mechanism underlying their inhibitory action on fibrosis. Methods: Exosome was collected from MSCs by ultracentrifugation method. We examined the suppressive effect of MSCs-derived exosome on skin fibrosis in bleomycin-induced SSc mouse model. Skin samples from the injected site were collected for further examination, and micro-RNA analysis of MSCs-derived exosome was performed. Results: Injection of MSCs-derived exosomes significantly inhibited bleomycin-induced dermal fibrosis in mice. MSCs-derived exosomes significantly reduced the amount of collagen and the number of alpha-SMA+ myofibroblasts and CD68+ macrophages in lesional skin. They also reduced the expression of type I collagen and TGF-beta receptor 1 in fibroblasts in vitro. Moreover, micro-RNA analysis revealed that several microRNAs in MSCs-derived exosomes have antifibrotic potential. We confirmed that overexpression of miR-196b-5p in fibroblasts significantly suppressed collagen type I alpha 2 expression. Conclusion: This study demonstrated that inhibition of collagen type I expression by miR-196b-5p in exosomes might be one of the mechanisms by which MSCs suppress skin fibrosis in an SSc mouse model. (c) 2021 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.