Bone Marrow Endothelial Progenitor Cells Are the Cellular Mediators of Pulmonary Hypertension in the Murine Monocrotaline Injury Model.
Bone Marrow Endothelial Progenitor Cells Are the Cellular Mediators of Pulmonary Hypertension in the Murine Monocrotaline Injury Model.
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DOI：
10.1002/sctm.16-0386
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发表时间：
2017-07
影响因子：
6
通讯作者：
Quesenberry PJ
中科院分区：
文献类型：
--
作者：
Aliotta JM;Pereira M;Wen S;Dooner MS;Del Tatto M;Papa E;Cheng Y;Goldberg L;Ventetuolo CE;Liang O;Klinger JR;Quesenberry PJ
骨髓细胞在调节肺动脉高压反应中的作用尚不清楚。确定骨髓来源的内皮祖细胞（EPCs）是否会诱导肺动脉高压（PH），以及间充质干细胞（MSC）来源的细胞外囊泡（ev）是否会减轻肺动脉高压。研究了三种基底细胞群：(a)来自载药和单鬼碱（MCT）处理的小鼠的基底细胞群（PH诱导），(b)来自载药和MCT处理的小鼠，在载药和MCT处理后接受MSC - EV输注（PH逆转，体内），(c)来自载药和MCT处理的MSC - EV培养的小鼠的基底细胞群（PH逆转，体外）。BM被分离成EPCs （sca‐1+/c‐kit+/VEGFR2+）和non - EPCs （sca‐1‐/c‐kit‐/VEGFR2‐），并移植到健康小鼠体内。右心室（RV）肥大通过右心室与左心室+中隔（RV/LV+S）比值评估，肺血管重构通过血管壁厚度与直径（WT/D）比值评估。MCT诱导的PH （MCT‐PH）小鼠的EPCs而非非EPCs增加了健康小鼠（PH诱导）的RV/LV+S， WT/D比率。MSC - ev处理MCT - PH小鼠的EPCs没有增加健康小鼠的RV/LV+S， WT/D比率（体内PH逆转）。同样，MCT - PH小鼠的EPCs经MSC - EVs预移植处理后，健康小鼠的RV/LV+S、WT/D比率并未增加（体外PH逆转）。在MCT - PH小鼠中，MSC - EV输注逆转了BM - EPCs的增加和肺组织中EPC基因及其受体/配体的表达增加。这些发现表明，BM的肺动脉高压作用是由EPCs介导的，而MSC - ev则减弱了这种作用。这些发现为PH的发病机制提供了新的见解，并为开发新的PH治疗方法提供了潜在的靶点。干细胞转化医学2017；6:1595 - 1606
The role of bone marrow (BM) cells in modulating pulmonary hypertensive responses is not well understood. Determine if BM‐derived endothelial progenitor cells (EPCs) induce pulmonary hypertension (PH) and if this is attenuated by mesenchymal stem cell (MSC)‐derived extracellular vesicles (EVs). Three BM populations were studied: (a) BM from vehicle and monocrotaline (MCT)‐treated mice (PH induction), (b) BM from vehicle‐, MCT‐treated mice that received MSC‐EV infusion after vehicle, MCT treatment (PH reversal, in vivo), (c) BM from vehicle‐, MCT‐treated mice cultured with MSC‐EVs (PH reversal, in vitro). BM was separated into EPCs (sca‐1+/c‐kit+/VEGFR2+) and non‐EPCs (sca‐1‐/c‐kit‐/VEGFR2‐) and transplanted into healthy mice. Right ventricular (RV) hypertrophy was assessed by RV‐to‐left ventricle+septum (RV/LV+S) ratio and pulmonary vascular remodeling by blood vessel wall thickness‐to‐diameter (WT/D) ratio. EPCs but not non‐EPCs from mice with MCT‐induced PH (MCT‐PH) increased RV/LV+S, WT/D ratios in healthy mice (PH induction). EPCs from MCT‐PH mice treated with MSC‐EVs did not increase RV/LV+S, WT/D ratios in healthy mice (PH reversal, in vivo). Similarly, EPCs from MCT‐PH mice treated with MSC‐EVs pre‐transplantation did not increase RV/LV+S, WT/D ratios in healthy mice (PH reversal, in vitro). MSC‐EV infusion reversed increases in BM‐EPCs and increased lung tissue expression of EPC genes and their receptors/ligands in MCT‐PH mice. These findings suggest that the pulmonary hypertensive effects of BM are mediated by EPCs and those MSC‐EVs attenuate these effects. These findings provide new insights into the pathogenesis of PH and offer a potential target for development of novel PH therapies. Stem Cells Translational Medicine 2017;6:1595–1606
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