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Mesenchymal stromal cell-derived exosomes improve pulmonary hypertension through inhibition of pulmonary vascular remodeling
Respiratory Research ( IF 5.8 ) Pub Date : 2020-03-20 , DOI: 10.1186/s12931-020-1331-4
Shanshan Zhang , Xiaoli Liu , Li Li Ge , Kailin Li , Yongchao Sun , Fang Wang , Ying Han , Chao Sun , Jue Wang , Wen Jiang , Qian Xin , Chaoyue Xu , Yuan Chen , Ou chen , Zhaohua Zhang , Yun Luan

Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling, right ventricular hypertrophy and failure. So far no effective treatment exists for this disease; hence, novel approaches are urgently needed. The aim of the present research was to observe the treatment effect of mesenchymal stromal cell derived exosomes and reveal the mechanism. Monocrotaline (MCT)-induced PH in rats and hypoxia-induced cell damage model were established, respectively. Exosomes derived from the supernatant of human umbilical cord mesenchymal stem cells (MSC-exo) were injected into MCT-PH model rat or added into the cells cultured medium. Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot methods were used in vivo and vitro. The results showed that MSC-exo could significantly attenuate right ventricular (RV) hypertrophy and pulmonary vascular remodelling in MCT-PH rats. In the cell culture experiments, we found that MSC-exo could significantly inhibit hypoxia-induced pulmonary arterial endothelial cell (PAEC) apoptosis and pulmonary arterial smooth muscle cells (PASMC) proliferation. Furthermore, the pulmonary arterioles endothelial-to-mesenchymal transition (EndMT) was obviously suppressed. Moreover, the present study suggest that MSC-exo can significantly upregulate the expression of Wnt5a in MCT-PH rats and hypoxic pulmonary vascular cells. Furthermore, with Wnt5a gene silencing, the therapeutic effect of MSC-exo against hypoxia injury was restrained. Synthetically, our data provide a strong evidence for the therapeutic of MSC-exo on PH, more importantly, we confirmed that the mechanism was associated with up-regulation of the expression of Wnt5a. These results offer a theoretical basis for clinical prevention and treatment of PH.

中文翻译:

间充质基质细胞来源的外泌体通过抑制肺血管重塑改善肺动脉高压

肺动脉高压(PH)是一种威胁生命的疾病,其特征是肺血管重构,右室肥大和衰竭。到目前为止,尚无对该病的有效治疗方法。因此,迫切需要新颖的方法。本研究的目的是观察间充质基质细胞来源的外泌体的治疗效果并揭示其机制。分别建立了由芥子油碱(MCT)诱导的大鼠PH和缺氧诱导的细胞损伤模型。将源自人脐带间充质干细胞(MSC-exo)上清液的外泌体注射到MCT-PH模型大鼠中或添加到细胞培养基中。在体内和体外使用免疫组织化学,实时定量聚合酶链反应(qRT-PCR)和蛋白质印迹法。结果表明,MSC-exo可以显着减轻MCT-PH大鼠的右室肥大和肺血管重构。在细胞培养实验中,我们发现MSC-exo可以显着抑制缺氧诱导的肺动脉内皮细胞(PAEC)凋亡和肺动脉平滑肌细胞(PASMC)增殖。此外,肺小动脉内皮向间质转化(EndMT)也明显受到抑制。此外,本研究表明,MSC-exo可以显着上调MCT-PH大鼠和缺氧性肺血管细胞中Wnt5a的表达。此外,通过Wnt5a基因沉默,抑制了MSC-exo对缺氧损伤的治疗作用。综合而言,我们的数据为MSC-exo在PH上的治疗提供了有力的证据,更重要的是,我们证实该机制与Wnt5a表达的上调有关。这些结果为临床预防和治疗PH提供了理论依据。
更新日期:2020-04-22
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