Transplantation of Mesenchymal Stem Cells Attenuates Pulmonary Hypertension by Normalizing the Endothelial-to-Mesenchymal Transition
Transplantation of Mesenchymal Stem Cells Attenuates Pulmonary Hypertension by Normalizing the Endothelial-to-Mesenchymal Transition
复制标题
间充质干细胞移植通过使内皮向间充质转化正常化来减轻肺动脉高压
DOI：
10.1165/rcmb.2018-0165oc
复制
发表时间：
2020
影响因子：
6.4
通讯作者：
Wang Jian
中科院分区：
文献类型：
--
作者：
Huang Junyi;Lu Wenju;Ouyang Haiping;Chen Yuqin;Zhang Chenting;Luo Xiaoyun;Li Meichan;Shu Jiaze;Zheng Qiuyu;Chen Haixia;Chen Jiyuan;Tang Haiyang;Sun Dejun;Yuan Jason X-J;Yang Kai;Wang Jian
几十年来，干细胞治疗肺动脉高压（PH）已从实验室假设发展到临床实践。大量的临床前研究为间充质干细胞（mesenchymal stem cells，MSCs）治疗肺动脉高压的临床应用奠定了理论和实践基础。然而，对潜在的机制仍然知之甚少。为了研究MSCs对PH的治疗作用及其机制，在体内实验中，将GFP+MSCs移植到慢性低氧诱导的PH（CHPH）大鼠模型肺组织中，在不同时间点进行追踪。在CHPH和Sugen缺氧诱导的PH模型中评估MSC对PH发病机制的影响。体外培养原代肺微血管内皮细胞，用MSC条件培养液处理。测定内皮-间质转化（EndMT）和细胞迁移特性的特异性标志物。MSCs可降低CHPH和Sugen缺氧诱导的PH大鼠肺动脉压，减轻胶原沉积，减轻肺动脉增厚和肌化。然后，MSC显着减弱缺氧诱导的肺PH模型和原代培养的大鼠肺微血管内皮细胞中的EndMT，反映了增加的间充质细胞标志物（纤连蛋白1和波形蛋白）和减少的内皮细胞标志物（血管内皮钙粘蛋白和血小板内皮细胞粘附分子-1）。此外，MSC还显著抑制缺氧诱导因子-2 α的蛋白表达和降解，这是已知的触发EndMT进展。我们的数据表明，MSC通过改善肺血管重塑、炎症和EndMT成功地预防PH。骨髓间充质干细胞移植可能是一个强大的治疗方法对PH。
For decades, stem cell therapies for pulmonary hypertension (PH) have progressed from laboratory hypothesis to clinical practice. Promising preclinical investigations have laid both a theoretical and practical foundation for clinical application of mesenchymal stem cells (MSCs) for PH therapy. However, the underlying mechanisms are still poorly understood. We sought to study the effects and mechanisms of MSCs on the treatment of PH. Forin vivoexperiments, the transplanted GFP+MSCs were traced at different time points in the lung tissue of a chronic hypoxia–induced PH (CHPH) rat model. The effects of MSCs on PH pathogenesis were evaluated in both CHPH and sugen hypoxia–induced PH models. Forin vitroexperiments, primary pulmonary microvascular endothelial cells were cultured and treated with the MSC conditioned medium. The specific markers of endothelial-to-mesenchymal transition (EndMT) and cell migration properties were measured. MSCs decreased pulmonary arterial pressure and ameliorated the collagen deposition, and reduced the thickening and muscularization in both CHPH and sugen hypoxia–induced PH rat models. Then, MSCs significantly attenuated the hypoxia-induced EndMT in both the lungs of PH models and primary cultured rat pulmonary microvascular endothelial cells, as reflected by increased mesenchymal cell markers (fibronectin 1 and vimentin) and decreased endothelial cell markers (vascular endothelial cadherin and platelet endothelial cell adhesion molecule-1). Moreover, MSCs also markedly inhibited the protein expression and degradation of hypoxia-inducible factor-2α, which is known to trigger EndMT progression. Our data suggest that MSCs successfully prevent PH by ameliorating pulmonary vascular remodeling, inflammation, and EndMT. Transplantation of MSCs could potentially be a powerful therapeutic approach against PH.