Thy-1 dependent uptake of mesenchymal stem cell-derived extracellular vesicles blocks myofibroblastic differentiation.
Thy-1 dependent uptake of mesenchymal stem cell-derived extracellular vesicles blocks myofibroblastic differentiation.
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DOI：
10.1038/s41598-017-18288-9
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发表时间：
2017-12-22
影响因子：
4.6
通讯作者：
Hagood JS
中科院分区：
文献类型：
--
作者：
Shentu TP;Huang TS;Cernelc-Kohan M;Chan J;Wong SS;Espinoza CR;Tan C;Gramaglia I;van der Heyde H;Chien S;Hagood JS
骨髓间充质干细胞（MSC）已被推广用于多种治疗应用。MSC的许多有益作用是旁分泌的，依赖于细胞外囊泡（EV）。尽管MSC衍生的EV（mEV）对急性肺损伤和肺纤维化有益，但肺成纤维细胞摄取mEV的机制及其对成肌纤维细胞分化的影响尚未建立。我们证明mEV，而不是成纤维细胞EV（fEV），抑制TGFβ1诱导的正常和特发性肺纤维化（IPF）肺成纤维细胞的肌纤维母细胞分化。与fEV相比，MEV显示出增加的时间和剂量依赖性细胞摄取。去除或阻断Thy-1，或阻断Thy-1-β整合素相互作用，可降低mEV摄取，并阻止成肌纤维细胞分化的抑制。微RNA（miR）199 a/B-3 p、21- 5 p、630、22- 3 p、196 a-5 p、199 B-5 p、34 a-5 p和148 a-3 p被选择性地包装在mEV中。计算机模拟分析表明，IPF肺成纤维细胞增加了mEV富集miR靶基因的表达。miR-630模拟物阻断了正常和IPF成纤维细胞中TGFβ1对CDH 2的诱导，并且miR-630消除了mEV对CDH 2表达的影响。这些数据表明，Thy-1与β整联蛋白的相互作用介导肺成纤维细胞对mEV的摄取，这阻断了成肌纤维细胞分化，并且mEV富含靶向IPF成纤维细胞中上调的促纤维化基因的miR。
Bone marrow-derived mesenchymal stem cells (MSC) have been promoted for multiple therapeutic applications. Many beneficial effects of MSCs are paracrine, dependent on extracellular vesicles (EVs). Although MSC-derived EVs (mEVs) are beneficial for acute lung injury and pulmonary fibrosis, mechanisms of mEV uptake by lung fibroblasts and their effects on myofibroblastic differentiation have not been established. We demonstrate that mEVs, but not fibroblast EVs (fEVs), suppress TGFβ1-induced myofibroblastic differentiation of normal and idiopathic pulmonary fibrosis (IPF) lung fibroblasts. MEVs display increased time- and dose-dependent cellular uptake compared to fEVs. Removal or blocking of Thy-1, or blocking Thy-1-beta integrin interactions, decreased mEV uptake and prevented suppression of myofibroblastic differentiation. MicroRNAs (miRs) 199a/b-3p, 21-5p, 630, 22-3p, 196a-5p, 199b-5p, 34a-5p and 148a-3p are selectively packaged in mEVs. In silico analyses indicated that IPF lung fibroblasts have increased expression of genes that are targets of mEV-enriched miRs. MiR-630 mimics blocked TGFβ1 induction of CDH2 in normal and IPF fibroblasts, and antagomiR-630 abrogated the effect of mEV on CDH2 expression. These data suggest that the interaction of Thy-1 with beta integrins mediates mEV uptake by lung fibroblasts, which blocks myofibroblastic differentiation, and that mEVs are enriched for miRs that target profibrotic genes up-regulated in IPF fibroblasts.
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DOI：
10.1016/j.bbamcr.2008.10.004
发表时间：
2009-05
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Barker TH;Hagood JS
通讯作者：
Hagood JS
影响因子：
3.7
作者：
Bruno S;Grange C;Collino F;Deregibus MC;Cantaluppi V;Biancone L;Tetta C;Camussi G
通讯作者：
Camussi G
影响因子：
6.1
作者：
Gatti, Stefano;Bruno, Stefania;Camussi, Giovanni
通讯作者：
Camussi, Giovanni
影响因子：
6.1
作者：
Biancone, Luigi;Bruno, Stefania;Camussi, Giovanni
通讯作者：
Camussi, Giovanni
影响因子：
4.5
作者：
Lino Cardenas CL;Henaoui IS;Courcot E;Roderburg C;Cauffiez C;Aubert S;Copin MC;Wallaert B;Glowacki F;Dewaeles E;Milosevic J;Maurizio J;Tedrow J;Marcet B;Lo-Guidice JM;Kaminski N;Barbry P;Luedde T;Perrais M;Mari B;Pottier N
通讯作者：
Pottier N