Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132.
Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132.
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DOI：
10.1161/circresaha.111.251546
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发表时间：
2011-09-30
影响因子：
20.1
通讯作者：
Madeddu P
中科院分区：
文献类型：
--
作者：
Katare R;Riu F;Mitchell K;Gubernator M;Campagnolo P;Cui Y;Fortunato O;Avolio E;Cesselli D;Beltrami AP;Angelini G;Emanueli C;Madeddu P
周细胞是血管成熟的关键调节细胞，但它们在心脏修复中的价值尚不清楚。我们研究了隐静脉来源的周细胞前体细胞(SVPs)在小鼠心肌梗死(MI)模型中的治疗活性和机制靶点。SVP免疫原性低，耐缺氧/饥饿(H/S)。与赋形剂相比，将SVPs移植到免疫缺陷CD1/Foxn-1NU/nu或免疫活性CD1小鼠的梗死区周围可以减轻左心室的扩张和改善射血分数。此外，SVPS还可减少心肌瘢痕、心肌细胞凋亡和间质纤维化，改善心肌血流量和新生血管，并降低血管通透性。SVPs通过募集表达血管内皮生长因子B的单核细胞，分泌血管内皮生长因子A、血管生成素-1和趋化因子，并诱导宿主的内源性血管分泌反应。供者和受者来源的刺激的联合激活了促血管生成和生存的Akt/eNOS/Bcl2信号通路。此外，MicroRNA-132(miR-132)是由SVP结构性表达和分泌的，在H/S或血管内皮生长因子B刺激下，它与其转录激活因子cAMP反应元件结合蛋白一起显著上调。我们接下来研究了SVP分泌的miR-132是否在心脏愈合中起旁分泌激活剂的作用。体外研究表明，SVP条件培养液通过抑制Ras-GTP酶激活蛋白和甲基-CpG结合蛋白2而刺激内皮管的形成和减少肌成纤维细胞的分化，这两个蛋白是被证实为miR-132靶点的。此外，用抗miR-132抑制miR-132会降低SVP的能力，从而改善梗塞心脏的收缩能力、修复性血管生成和间质纤维化。SVP移植通过一种新的旁分泌机制产生长期的心功能改善，该机制涉及miR-132的分泌及其靶基因的抑制。
Pericytes are key regulators of vascular maturation, but their value for cardiac repair remains unknown. We investigated the therapeutic activity and mechanistic targets of saphenous vein-derived pericyte progenitor cells (SVPs) in a mouse myocardial infarction (MI) model. SVPs have a low immunogenic profile and are resistant to hypoxia/starvation (H/S). Transplantation of SVPs into the peri-infarct zone of immunodeficient CD1/Foxn-1nu/nu or immunocompetent CD1 mice attenuated left ventricular dilatation and improved ejection fraction compared to vehicle. Moreover, SVPs reduced myocardial scar, cardiomyocyte apoptosis and interstitial fibrosis, improved myocardial blood flow and neovascularization, and attenuated vascular permeability. SVPs secrete vascular endothelial growth factor A, angiopoietin-1, and chemokines and induce an endogenous angiocrine response by the host, through recruitment of vascular endothelial growth factor B expressing monocytes. The association of donor- and recipient-derived stimuli activates the proangiogenic and prosurvival Akt/eNOS/Bcl-2 signaling pathway. Moreover, microRNA-132 (miR-132) was constitutively expressed and secreted by SVPs and remarkably upregulated, together with its transcriptional activator cyclic AMP response element-binding protein, on stimulation by H/S or vascular endothelial growth factor B. We next investigated if SVP-secreted miR-132 acts as a paracrine activator of cardiac healing. In vitro studies showed that SVP conditioned medium stimulates endothelial tube formation and reduces myofibroblast differentiation, through inhibition of Ras-GTPase activating protein and methyl-CpG-binding protein 2, which are validated miR-132 targets. Furthermore, miR-132 inhibition by antimiR-132 decreased SVP capacity to improve contractility, reparative angiogenesis, and interstitial fibrosis in infarcted hearts. SVP transplantation produces long-term improvement of cardiac function through a novel paracrine mechanism involving the secretion of miR-132 and inhibition of its target genes.