Exosomes derived from miR-181-5p-modified adipose-derived mesenchymal stem cells prevent liver fibrosis via autophagy activation.
Exosomes derived from miR-181-5p-modified adipose-derived mesenchymal stem cells prevent liver fibrosis via autophagy activation.
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miR-181-5p修饰的脂肪间充质干细胞衍生的外泌体通过自噬激活预防肝纤维化
DOI：
10.1111/jcmm.13170
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发表时间：
2017-10
影响因子：
5.3
通讯作者：
Lu L
中科院分区：
文献类型：
--
作者：
Qu Y;Zhang Q;Cai X;Li F;Ma Z;Xu M;Lu L
活化的肝星状细胞（HSC）通过分泌形成纤维性瘢痕组织的胶原来响应肝损伤，如果适当调节，其可导致肝硬化。微小RNA（miRNA）肝脏治疗的进展受到将miRNA递送至受损组织的困难的阻碍。然而，由脂肪来源的间充质干细胞（ADSC）分泌的外泌体可用于将miRNA递送至HSC。将ADSC工程化以过表达miRNA-181 - 5 p（miR-181 - 5 p-ADSC），以选择性地将外来体归巢至小鼠肝星状细胞（HST-T6）或CCl 4诱导的肝纤维化小鼠模型，并与非靶向对照秀丽隐杆线虫miR-67（cel-miR-67）-ADSC进行比较。体外分析证实，miR-181 - 5 p从miR-181 - 5 p-ADSC的转移通过分泌的外泌体摄取发生。在HST-T6细胞中使用cyc 3标记的pre-miRNA转染的ADSC（具有/不具有外泌体抑制剂GW 4869）观察外泌体。评估了miRNA-181 - 5 p过表达对纤维化相关的STAT 3/Bcl-2/Beclin 1通路和细胞外基质组分的影响。来自miR 181 - 5 p-ADSC的外泌体下调了HST-T6细胞中的Stat 3和Bcl-2，并激活了自噬。此外，与miR-67-ADSC外泌体相比，加入分离的miR-181 - 5 p-ADSC外泌体后，TGF-β1诱导的HST-T6细胞中纤维化基因的上调表达受到抑制。与对照组相比，外泌体治疗减轻了肝损伤，并显著下调了肝脏中的I型胶原、波形蛋白、α-SMA和纤连蛋白。总而言之，工程化ADSC的有效抗纤维化功能能够选择性地将miR-181 - 5 p转移到受损的肝细胞，并将为使用外泌体-ADSC治疗性递送靶向肝脏疾病的miRNA铺平道路。
Proliferating hepatic stellate cells (HSCs) respond to liver damage by secreting collagens that form fibrous scar tissue, which can lead to cirrhosis if in appropriately regulated. Advancement of microRNA (miRNA) hepatic therapies has been hampered by difficulties in delivering miRNA to damaged tissue. However, exosomes secreted by adipose‐derived mesenchymal stem cells (ADSCs) can be exploited to deliver miRNAs to HSCs. ADSCs were engineered to overexpress miRNA‐181‐5p (miR‐181‐5p‐ADSCs) to selectively home exosomes to mouse hepatic stellate (HST‐T6) cells or a CCl4‐induced liver fibrosis murine model and compared with non‐targeting control Caenorhabditis elegans miR‐67 (cel‐miR‐67)‐ADSCs. In vitro analysis confirmed that the transfer of miR‐181‐5p from miR‐181‐5p‐ADSCs occurred via secreted exosomal uptake. Exosomes were visualized in HST‐T6 cells using cyc3‐labelled pre‐miRNA‐transfected ADSCs with/without the exosomal inhibitor, GW4869. The effects of miRNA‐181‐5p overexpression on the fibrosis associated STAT3/Bcl‐2/Beclin 1 pathway and components of the extracellular matrix were assessed. Exosomes from miR181‐5p‐ADSCs down‐regulated Stat3 and Bcl‐2 and activated autophagy in the HST‐T6 cells. Furthermore, the up‐regulated expression of fibrotic genes in HST‐T6 cells induced by TGF‐β1 was repressed following the addition of isolated miR181‐5p‐ADSC exosomes compared with miR‐67‐ADSCexosomes. Exosome therapy attenuated liver injury and significantly down‐regulated collagen I, vimentin, α‐SMA and fibronectin in liver, compared with controls. Taken together, the effective anti‐fibrotic function of engineered ADSCs is able to selectively transfer miR‐181‐5p to damaged liver cells and will pave the way for the use of exosome‐ADSCs for therapeutic delivery of miRNA targeting liver disease.
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影响因子：
1.8
作者：
Luna AC;Madeira ME;Conceição TO;Moreira JA;Laiso RA;Maria DA
通讯作者：
Maria DA
影响因子：
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影响因子：
13.6
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影响因子：
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作者：
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影响因子：
3.2
作者：
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通讯作者：
Friedman, Scott L.