Mesenchymal Stem Cell Extracellular Vesicles Reverse Sugen/Hypoxia Pulmonary Hypertension in Rats
Mesenchymal Stem Cell Extracellular Vesicles Reverse Sugen/Hypoxia Pulmonary Hypertension in Rats
复制标题
骨髓间充质干细胞细胞外囊泡逆转大鼠Sugen/缺氧性肺动脉高压
DOI：
10.1165/rcmb.2019-0154oc
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发表时间：
2020-05-01
影响因子：
6.4
通讯作者：
Liang, Olin D.
中科院分区：
文献类型：
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作者：
Klinger, James R.;Pereira, Mandy;Liang, Olin D.
间充质干细胞细胞外囊泡可减轻肺动脉高压，但其在较大动物模型中逆转已建立疾病的能力及其作用的持续时间和机制尚不清楚。我们试图确定间充质干细胞的细胞外囊泡在减轻Sugen/缺氧诱导的肺动脉高压大鼠的肺动脉高压中的功效和机制。在皮下注射Sugen 5416和暴露于3周缺氧之前或之后，通过尾静脉注射用间充质干细胞细胞外囊泡或等体积的生理盐水媒介物处理雄性大鼠。通过右心室收缩压、右心室重量与左心室+室间隔重量之比和外周肺血管肌化来评估肺动脉高压。免疫组化法检测巨噬细胞的活化状态和向肺的募集。在诱导肺动脉高压之前或之后注射间充质干细胞细胞外囊泡使右心室压力正常化，并减少右心室肥大和外周肺血管的肌肉化。该效应在一系列剂量和给药间隔内是一致的，并且与肺巨噬细胞数量减少、替代活化巨噬细胞与经典活化巨噬细胞的比率较高相关。（M2/M1 = 2.00 +/- 0.14 vs. 1.09 +/- 0.11; P< 0.01），外周血管数量增加（每个视野11.8 +/- 0.66 vs. 6.9 +/- 0.57血管; P< 0.001）。间充质干细胞细胞外囊泡可有效预防和逆转Sugen/缺氧性肺动脉高压的肺动脉高压，为肺动脉高压的治疗提供了新的途径。
Mesenchymal stem cell extracellular vesicles attenuate pulmonary hypertension, but their ability to reverse established disease in larger animal models and the duration and mechanism(s) of their effect are unknown. We sought to determine the efficacy and mechanism of mesenchymal stem cells' extracellular vesicles in attenuating pulmonary hypertension in rats with Sugen/hypoxia-induced pulmonary hypertension. Male rats were treated with mesenchymal stem cell extracellular vesicles or an equal volume of saline vehicle by tail vein injection before or after subcutaneous injection of Sugen 5416 and exposure to 3 weeks of hypoxia. Pulmonary hypertension was assessed by right ventricular systolic pressure, right ventricular weight to left ventricle+septum weight, and muscularization of peripheral pulmonary vessels. Immunohistochemistry was used to measure macrophage activation state and recruitment to lung. Mesenchymal stem cell extracellular vesicles injected before or after induction of pulmonary hypertension normalized right ventricular pressure and reduced right ventricular hypertrophy and muscularization of peripheral pulmonary vessels. The effect was consistent over a range of doses and dosing intervals and was associated with lower numbers of lung macrophages, a higher ratio of alternatively to classically activated macrophages (M2/M1 = 2.00 +/- 0.14 vs. 1.09 +/- 0.11; P< 0.01), and increased numbers of peripheral blood vessels (11.8 +/- 0.66 vs. 6.9 +/- 0.57 vessels per field; P< 0.001). Mesenchymal stem cell extracellular vesicles are effective at preventing and reversing pulmonary hypertension in Sugen/hypoxia pulmonary hypertension and may offer a new approach for the treatment of pulmonary arterial hypertension.