Exosomes induce and reverse monocrotaline-induced pulmonary hypertension in mice
Exosomes induce and reverse monocrotaline-induced pulmonary hypertension in mice
复制标题
DOI：
10.1093/cvr/cvw054
复制
发表时间：
2016-06-01
影响因子：
10.8
通讯作者：
Klinger, James R.
中科院分区：
文献类型：
--
作者：
Aliotta, Jason M.;Pereira, Mandy;Klinger, James R.
来自单核细胞碱（MCT）诱导的肺动脉高压（PH）小鼠的细胞外囊泡（ev）在健康小鼠中诱导PH，来自间充质干细胞（MSCs）的ev的外泌体（EXO）部分可以减弱缺氧PH的发展。我们试图确定ev的EXO部分是否负责调节肺血管反应，以及EXO- mir含量的差异是否解释了来自MSCs和MCT-PH小鼠的EXO的差异作用。将MCT-PH小鼠和对照小鼠的血浆、肺EVs分成EXO（外泌体）和微囊泡（MV）部分，注射到健康小鼠体内。将MSCs的ev分成EXO、MV部分，注射到mct处理小鼠体内。通过右心室与左心室+间隔（RV/LV + S）比值和肺动脉壁厚/直径（WT/D）比值评估PH。miR微阵列分析也在所有EXO人群中进行。mct损伤小鼠的exo而非MVs增加了健康小鼠的RV/LV + S、WT/D比率。MCT注射时给药的MSC-EXOs阻止了RV/LV + S、WT/D比值的增加，并逆转了MCT给药后这些比值的增加。mct损伤小鼠和特发性肺动脉高压（IPAH）患者的exo含有增加的miRs-19b、-20a、-20b和-145水平，而从msc - exo中分离的miRs具有增加的抗炎、抗增殖miRs水平，包括miRs-34a、-122、-124和-127。这些发现表明，循环或msc - exo可能根据其miR货量调节肺动脉高压的作用。msc - exo逆转MCT-PH的能力为新的PAH治疗提供了一个有希望的潜在靶点。
Extracellular vesicles (EVs) from mice with monocrotaline (MCT)-induced pulmonary hypertension (PH) induce PH in healthy mice, and the exosomes (EXO) fraction of EVs from mesenchymal stem cells (MSCs) can blunt the development of hypoxic PH. We sought to determine whether the EXO fraction of EVs is responsible for modulating pulmonary vascular responses and whether differences in EXO-miR content explains the differential effects of EXOs from MSCs and mice with MCT-PH.Plasma, lung EVs from MCT-PH, and control mice were divided into EXO (exosome), microvesicle (MV) fractions and injected into healthy mice. EVs from MSCs were divided into EXO, MV fractions and injected into MCT-treated mice. PH was assessed by right ventricle-to-left ventricle + septum (RV/LV + S) ratio and pulmonary arterial wall thickness-to-diameter (WT/D) ratio. miR microarray analyses were also performed on all EXO populations. EXOs but not MVs from MCT-injured mice increased RV/LV + S, WT/D ratios in healthy mice. MSC-EXOs prevented any increase in RV/LV + S, WT/D ratios when given at the time of MCT injection and reversed the increase in these ratios when given after MCT administration. EXOs from MCT-injured mice and patients with idiopathic pulmonary arterial hypertension (IPAH) contained increased levels of miRs-19b,-20a,-20b, and -145, whereas miRs isolated from MSC-EXOs had increased levels of anti-inflammatory, anti-proliferative miRs including miRs-34a,-122,-124, and -127.These findings suggest that circulating or MSC-EXOs may modulate pulmonary hypertensive effects based on their miR cargo. The ability of MSC-EXOs to reverse MCT-PH offers a promising potential target for new PAH therapies.