MSC Transplantation Attenuates Inflammation, Prevents Endothelial Damage and Enhances the Angiogenic Potency of Endogenous MSCs in a Model of Pulmonary Arterial Hypertension.
MSC Transplantation Attenuates Inflammation, Prevents Endothelial Damage and Enhances the Angiogenic Potency of Endogenous MSCs in a Model of Pulmonary Arterial Hypertension.
复制标题
间充质干细胞移植可减轻肺动脉高压模型中的炎症、防止内皮损伤并增强内源性间充质干细胞的血管生成能力
DOI：
10.2147/jir.s355479
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发表时间：
2022
影响因子：
4.5
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Shao F;Liu R;Tan X;Zhang Q;Ye L;Yan B;Zhuang Y;Xu J
目的肺动脉高压(PAH)是一种由内皮功能障碍引起的进展性、致死性肺血管疾病。间充质基质细胞(MSCs)已被证明可以改善各种啮齿动物模型中的PAH；然而，这些模型并不能概括人类PAH中观察到的所有组织病理学变化。肉鸡(Gallus Gallus)可以自发地发展为PAH，并伴有与人类患者极其相似的新生内膜和丛源性动脉病变。在此，我们研究了骨髓间充质干细胞移植对该动物模型中PAH发生的保护作用。方法15日龄混杂肉鸡静脉注射2×106骨髓间充质干细胞或PBS。一天后，鸟类被暴露在凉爽的温度中，饮用水中含有过量的盐，以诱导PAH。记录PAH的累积发病率和右/左心室比率。评估肺组织学特征是否存在内皮细胞损伤、内皮细胞增殖和丛状病变。检测肺组织中促炎症介质和血管生成因子的表达。Matrigel管形成实验检测内源性MSCs的血管生成潜能。结果MSC可降低PAH累积发病率，减轻肺内皮细胞损伤、丛状病变和炎性介质的产生。旁分泌血管生成因子包括血管内皮生长因子-A和转化生长因子-β的表达在不同组间无显著差异，提示它们对骨髓间充质干细胞移植的有益效果不是必需的。有趣的是，接受MSC移植的鸟类的内源性MSCs在体外显示出向内皮分化的能力，而来自模拟鸟类的内源性MSCs没有。结论本研究结果支持骨髓间充质干细胞移植治疗PAH，提示外源性MSCs通过调节炎症反应和内源性MSC介导的血管修复而产生有益的作用。
Purpose Pulmonary arterial hypertension (PAH) is a progressive and fatal pulmonary vascular disease initiated by endothelial dysfunction. Mesenchymal stromal cells (MSCs) have been shown to ameliorate PAH in various rodent models; however, these models do not recapitulate all the histopathological alterations observed in human PAH. Broiler chickens (Gallus gallus) can develop PAH spontaneously with neointimal and plexogenic arteriopathy strikingly similar to that in human patients. Herein, we examined the protective effects of MSC transplantation on the development of PAH in this avian model. Methods Mixed-sex broilers at 15 d of age were received 2×106 MSCs or PBS intravenously. One day later, birds were exposed to cool temperature with excessive salt in their drinking water to induce PAH. Cumulative morbidity from PAH and right-to-left ventricle ratio were recorded. Lung histologic features were evaluated for the presence of endothelial damage, endothelial proliferation and plexiform lesions. Expression of proinflammatory mediators and angiogenic factors in the lung was detected. Matrigel tube formation assay was performed to determine the angiogenic potential of endogenous MSCs. Results MSC administration reduced cumulative PAH morbidity and attenuated endothelial damage, plexiform lesions and production of inflammatory mediators in the lungs. No significant difference in the expression of paracrine angiogenic factors including VEGF-A and TGF-β was determined between groups, suggesting that they are not essential for the beneficial effect of MSC transplantation. Interestingly, the endogenous MSCs from birds receiving MSC transplantation demonstrated endothelial differentiatial capacity in vitro whereas those from the mock birds did not. Conclusion Our results support the therapeutic use of MSC transplantation for PAH treatment and suggest that exogenous MSCs produce beneficial effects through modulating inflammation and endogenous MSC-mediated vascular repair.