Exosomes derived from human adipose mesenchymal stem cells attenuate hypertrophic scar fibrosis by miR-192-5p/IL-17RA/Smad axis.
Exosomes derived from human adipose mesenchymal stem cells attenuate hypertrophic scar fibrosis by miR-192-5p/IL-17RA/Smad axis.
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源自人脂肪间充质干细胞的外泌体通过 miR-192-5p/IL-17RA/Smad 轴减轻肥厚性疤痕纤维化
DOI：
10.1186/s13287-021-02290-0
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发表时间：
2021-03-31
影响因子：
7.5
通讯作者：
Hu D
中科院分区：
文献类型：
--
作者：
Li Y;Zhang J;Shi J;Liu K;Wang X;Jia Y;He T;Shen K;Wang Y;Liu J;Zhang W;Wang H;Zheng Z;Hu D
研究背景增生性瘢痕（hypertrophicscar，HS）是烧伤或创伤后真皮组织的纤维增生性病变，常导致患者的外观和功能障碍。近年来有证据表明ADSC-Exo能减轻内脏纤维化，但其在皮肤纤维化中的作用尚未引起足够的重视。在这项研究中，我们将探讨ADSC-Exo对HS的影响，并探讨其确切的机制下的properties.MethodsADSC-Exo的分离，鉴定，并内化HS衍生的成纤维细胞（HSFs）。流式细胞术、Ki 67免疫荧光染色、划痕法和trans-wells法检测ADSC-Exo对HSFs增殖和迁移的影响。采用RT-PCR、免疫印迹、免疫荧光和免疫组织化学染色法检测ADSC-Exo、miR-192- 5 p模拟物或抑制剂、IL-17 RA siRNA及其阴性对照刺激的HSFs中IL-17 RA、Col 1、Col 3、α-SMA、SIP 1和p-Smad 2/p-Smad 3的表达。结果ADSC-Exo能有效抑制HSFs的增殖和迁移，降低HSFs中Col 1、Col 3、α-SMA、IL-17 RA、p-Smad 2/p-Smad 3的表达，增加SIP 1的表达。此外，ADSC-Exo治疗组的小鼠表现出更快的伤口愈合和更少的胶原沉积。此外，miR-192- 5 p在ADSC-Exo中高度表达，ADSC-Exosomal miR-192- 5 p改善了增生性瘢痕纤维化。同时，miR-192- 5 p靶向IL-17 RA的表达以降低促纤维化蛋白水平。IL-17 RA在HS和HSFs中均过表达，敲低IL-17 RA可降低HSFs中Col 1、Col 3、α-SMA和p-Smad 2/p-Smad 3的表达，增加SIP 1的表达。最重要的是，IL-17 RA沉默也促进伤口愈合，衰减胶原蛋白的产生，并调制Smad通路在HSFs.ConclusionsThis研究说明ADSC-Exo衰减胶原蛋白的沉积，成纤维细胞转分化为肌成纤维细胞，并形成增生性瘢痕的体外和体内实验。ADSC-Exosomal miR-192- 5 p靶向IL-17 RA调节增生性瘢痕纤维化中的Smad通路ADSC-Exo可能是临床治疗增生性瘢痕的一种有前景的治疗策略，其抗纤维化作用可能通过miR-192- 5 p/IL-17 RA/Smad轴实现。
BackgroundHypertrophic scar (HS) is a fibro-proliferative disorder of dermis after burn or trauma and usually leads to esthetic disfiguration and functionary impairment for patients. Emerging evidences demonstrated ADSC-Exo could alleviate the visceral fibrosis, but little attention had been paid to its role in skin fibrosis. In the study, we would explore the effect of ADSC-Exo on HS and investigated the exact mechanism underlying the properties.MethodsADSC-Exo were isolated, identified, and internalized by HS-derived fibroblasts (HSFs). The effect of ADSC-Exo on the proliferation and migration of HSFs were detected by flow cytometry and Ki67 immunofluorescence staining, or scratch and trans-wells assays, respectively. RT-PCR, immunoblotting, immunofluorescence, and immunohistochemistry staining were used to evaluate the expression of IL-17RA, Col1, Col3, α-SMA, SIP1, and p-Smad2/p-Smad3 in HSFs stimulated with ADSC-Exo, miR-192-5p mimics, or inhibitors, IL-17RA siRNA and their negative controls. Digital morphology, H&E, Masson’s trichrome staining, and immunohistochemistry staining were performed to measure the effect of ADSC-Exo and Lv-IL-17RA shRNA on excisional wound of BALB/c mice.ResultsThe verified ADSC-Exo effectively inhibited the proliferation and migration of HSFs, decreased the expression of Col1, Col3, α-SMA, IL-17RA, and p-Smad2/p-Smad3 and increased the levels of SIP1 in HSFs. Besides, the mice in ADSC-Exo-treated group demonstrated faster wound healing and less collagen deposition. Furthermore, miR-192-5p was highly expressed in ADSC-Exo and ADSC-Exosomal miR-192-5p ameliorated hypertrophic scar fibrosis. Meanwhile, miR-192-5p targeted the expression of IL-17RA to decrease the pro-fibrotic proteins levels. Moreover, IL-17RA was overexpressed in HS and HSFs, and knockdown IL-17RA alleviated the expression of Col1, Col3, α-SMA, and p-Smad2/p-Smad3 and increased the expression of SIP1 in HSFs. Most importantly, IL-17RA silence also facilitated wound healing, attenuated collagen production, and modulated Smad pathway in HSFs.ConclusionsThis study illustrated ADSC-Exo attenuated the deposition of collagen, the trans-differentiation of fibroblasts-to-myofibroblasts, and the formation of hypertrophic scar by in vitro and in vivo experiments. ADSC-Exosomal miR-192-5p targeted IL-17RA to regulate Smad pathway in hypertrophic scar fibrosis. ADSC-Exo could be a promising therapeutic strategy for clinical treatment of hypertrophic scar and the anti-fibrotic properties could be achieved by miR-192-5p/IL-17RA/Smad axis.
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影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
IL-17在哮喘期间增强了原代人B细胞的趋化性。
影响因子：
3.7
作者：
Halwani R;Al-Kufaidy R;Vazquez-Tello A;Pureza MA;BaHammam AS;Al-Jahdali H;Alnassar SA;Hamid Q;Al-Muhsen S
通讯作者：
Al-Muhsen S
影响因子：
4.1
作者：
Lam, Mai T.;Nauta, Allison;Longaker, Michael T.
通讯作者：
Longaker, Michael T.
影响因子：
19.6
作者：
Kim, JH;Kim, BK;Lee, HS
通讯作者：
Lee, HS
DOI：
10.1111/j.1742-4658.2010.07632.x
发表时间：
2010-05
期刊：
The FEBS journal
影响因子：
--
作者：
Jiang X;Tsitsiou E;Herrick SE;Lindsay MA
通讯作者：
Lindsay MA