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首页> 外文期刊>Journal of Cellular Physiology >Cannabinoid Receptor 1 Mediates Homing of Bone Marrow-Derived Mesenchymal Stem Cells Triggered by Chronic Liver Injury
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Cannabinoid Receptor 1 Mediates Homing of Bone Marrow-Derived Mesenchymal Stem Cells Triggered by Chronic Liver Injury

机译:大麻素受体1介导归航的骨头骨髓来源间充质干细胞触发由慢性肝损伤

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Cannabinoid receptors (CBs) have been implicated in the pathogenesis of various liver diseases, including liver fibrosis. Our previous studies have demonstrated that after liver injury, mouse bone marrow-derived mesenchymal stem cells (BMSCs) can migrate to the injured liver and differentiate to myofibroblasts, contributing to hepatic fibrogenesis. However, the role of CBs in the homing of BMSCs in liver injury is yet unclear. In this study, we found that both CB1 and CB2 were expressed in BMSCs. Migration assays were performed by transwell chambers. CB1 agonist ACEA promoted the migration of BMSCs, but CB2 agonist JWH133 had no effect. Pharmacological or genetic ablation of CB1 reduced ACEA-induced migration, whereas CB2 did not. Moreover, activation of CB1 increased active GTP-bound Rac1, RhoA, and Cdc42 protein levels. The elevated GTP-bound Rac1 and RhoA protein levels were decreased by CB1 antagonist AM281 treatment, but not Cdc42. In addition, ACEA-induced migration was suppressed by NSC23766 (Rac1 inhibitor) or C3 transferase (RhoA inhibitor), whereas MLS-573151 (Cdc42 inhibitor) had no effect. Consistent with these data, Rac1 or RhoA knock-down significantly blocked CB1-mediated migration. Meanwhile, CB1-mediated migration was associated with cytoskeletal remodeling. In vivo, administration of CB1 antagonist AM281 markedly inhibited the recruitment of BMSCs to the injured liver using fluorescence-activated cell sorting. Furthermore, blockade of CB1 significantly attenuated liver fibrosis. In conclusion, our results suggest that CB1 plays a crucial role in liver fibrosis through mediating the homing of BMSCs to damaged liver, which may provide new insight into the pathogenesis and treatment of liver fibrosis. (C) 2016 Wiley Periodicals, Inc.
机译:大麻素受体(CBs)牵连其中在各种肝脏疾病的发病机制,包括肝纤维化。表明肝损伤后,老鼠骨骨髓来源间充质干细胞(综合)可以迁移到肝脏和受伤区分myofibroblasts,导致肝纤维发生。bmsc归航的肝损伤不清楚。和CB2 bmsc表达。是由transwell室。究其促进了bmsc的迁移,但CB2受体激动剂JWH133没有效果。的基因消融CB1 ACEA-induced减少迁移,而CB2没有。激活CB1 GTP-bound增加活跃Rac1、RhoA Cdc42蛋白水平。高架GTP-bound Rac1 RhoA蛋白质水平是减少了CB1拮抗剂AM281治疗,但不是Cdc42。迁移被NSC23766抑制(Rac1抑制剂)或C3转移酶(RhoA抑制剂),而mls - 573151 (Cdc42抑制剂)没有的效果。显著降低了CB1-mediated迁移。与细胞骨架重塑有关。管理CB1拮抗剂AM281明显抑制了招聘的bmsc受伤使用fluorescence-activated肝细胞排序。此外,CB1显著的封锁减毒肝纤维化。结果表明,CB1起着至关重要的作用通过中介的归航肝纤维化bmsc肝脏受损,这可能提供新的洞察的发病机理和治疗肝纤维化。

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