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首页 » 华人研究 » Exp Biol Med:国内研究发现更好利用间充质干细胞治疗心肌梗死的方法

Exp Biol Med:国内研究发现更好利用间充质干细胞治疗心肌梗死的方法

来源:生物谷 2014-03-19 21:02

2014年3月19日讯 /生物谷BIOON/--虽然移植骨髓间充质干细胞能改善心功能,有助于恢复受损的血管内皮细胞,间充质干细胞通过对血管平滑肌细胞直接或间接地作用诱导新生内膜增生。受体活性修饰蛋白1是降钙素基因相关肽的特异性受体。在体内和体外,降钙素基因相关肽及其受体参与细胞增殖和凋亡。外源性受体活性修饰蛋白1增强降钙素基因相关肽对血管平滑肌细胞增殖抑制的效果。

近日,国内遵义医学院研究人员报告称发现了更好地利用干细胞治疗梗死、改善心脏功能和动脉损害的方法,相关研究已经发表在Experimental Biology and Medicine杂志上。他们将间充质干细胞(MSCs)转染含有人受体活性修饰蛋白1(hRAMP1)基因( EGFP-hRAMP1-MSCS)的重组腺病毒,当转染后的MSCs移植到心肌梗死(MI)兔模型,与对照EGFP-MSCs移植组相比,大大改善了梗死心脏功能和内皮恢复。

MSCs具有良好的适用性,可用于进行细胞移植,因为他们拥有自我更新和多向分化潜能。接受环境或化学物质,干细胞可以分化成多种细胞类型。大量动物实验和小规模临床试验表明,MSC移植促进形成新的血管,以降低心肌梗死面积,并减少瘢痕组织和心室重塑的形成,以及改善心脏功能。然而,MSCs具有分化成平滑肌细胞,可能是血管损伤后新内膜形成过程中血管平滑肌细胞增殖的来源。最近研究发现,与单独施用MSCs相比,基因修饰MSCs,如血红素氧化酶1(HO-1)蛋白,粒细胞集落刺激因子(G-CSF)过表达的MSCs,已被证明能更有效的改善心肌梗死。

降钙素基因相关蛋白(CGRP)是最知名的血管扩张剂,能有力调节血管张力及血管功能等方面。CGRP的受体包括降钙素受体样受体(CRLR)、RAMP1。RAMP1赋予降钙素基因相关肽特异性配体。动脉响应CGRP产生的舒张效应依赖于RAMP1表达。当增加血管平滑肌细胞中RAMP1的表达,应对降钙素基因相关肽的响应增强。

RAMP1过度表达增加降钙素基因相关肽诱导的血管扩张,保护防止血管紧张素II诱导的血管内皮功能障碍和血管平滑肌细胞增殖。在这项研究中,研究人员通过心肌梗死再灌注和颈动脉损伤兔模型细胞移植,测试了人RAMP1-过度表达MSCs对梗死心脏功能及内膜增生的影响。数据表明,通过基因改造MSCs过度表达hRAMP1,显著抑制新生内膜增生,改善梗死心脏的功能。(生物谷Bioon.com)

doi:10.1177/1535370213517619
ransplantation of mesenchymal stem cells carrying the human receptor activity-modifying protein 1 gene improves cardiac function and inhibits neointimal proliferation in the carotid angioplasty and myocardial infarction rabbit model

Bei Shi,et al.

Although transplanting mesenchymal stem cells (MSCs) can improve cardiac function and contribute to endothelial recovery in a damaged artery, natural MSCs may induce neointimal hyperplasia by directly or indirectly acting on vascular smooth muscle cells (VSMCs). Receptor activity-modifying protein 1 (RAMP1) is the component and the determinant of ligand specificity of calcitonin gene-related peptide (CGRP). It is recently reported that CGRP and its receptor involve the proliferation and the apoptosisin vivo and in vitro, and the exogenous RAMP1 enhances the antiproliferation effect of CGRP in VSMCs. Here, we investigated the effects of MSCs overexpressing the human receptor activity-modifying protein 1 (hRAMP1) on heart function and artery repair in rabbit models of myocardial infarction (MI) reperfusion and carotid artery injury. MSCs transfected with a recombinant adenovirus containing the hRAMP1 gene (EGFP-hRAMP1-MSCs) were injected into the rabbit models via the ear vein at 24?h after carotid artery injury and MI 7 days post-EGFP-hRAMP1-MSC transplantation. The cells that expressed both enhance green fluorescent protein (EGFP) and CD31 were detected in the neointima of the damaged artery via immunofluorescence. EGFP-hRAMP1 expression was observed in the injured artery and infarcted myocardium by western blot analysis, confirming that the engineered MSCs targeted the injured artery and infarcted myocardium and expressed hRAMP1 protein. Compared with the EGFP-MSCs group, the EGFP-hRAMP1-MSCs group had a significantly smaller infarcted area and improved cardiac function by 28 days after cell transplantation, as detected by triphenyltetrazolium chloride staining and echocardiography. Additionally, arterial hematoxylin–eosin staining revealed that the area of the neointima and the area ratio of intima/media were significantly decreased in the EGFP-hRAMP1-MSCs group. An immunohistological study showed that the expression of α-smooth muscle antigen and proliferating cell nuclear antigen in the neointima cells of the carotid artery of the EGFP-hRAMP1-MSCs group was approximately 50% lower than that of the EGFP-MSCs group, suggesting that hRAMP1 expression may inhibit VSMCs proliferation within the neointima. Therefore, compared with natural MSCs, EGFP-hRAMP1-engineered MSCs improved infarcted heart function and endothelial recovery from artery injury more efficiently, which will provide valuable information for the development of MSC-based therapy.


 

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