Genetically manipulated progenitor cell sheet with diprotin A improves myocardial function and repair of infarcted hearts
Genetically manipulated progenitor cell sheet with diprotin A improves myocardial function and repair of infarcted hearts
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DOI：
10.1152/ajpheart.00592.2010
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发表时间：
2010-11-01
影响因子：
4.8
通讯作者：
Wang, Yigang
中科院分区：
文献类型：
--
作者：
Zhang, Dongsheng;Huang, Wei;Wang, Yigang
张D，黄W，戴B，赵T，阿什拉夫A，米勒德RW，阿什拉夫M，王Y。含二肽基肽酶 - 4抑制剂（Diprotin A）的基因修饰祖细胞片改善心肌功能及梗死心脏的修复。《美国生理学杂志 - 心脏和循环生理学》299卷：H1339 - H1347，2010年。首次发表于2010年8月27日；doi:10.1152/ajpheart.00592.2010。 - 我们假设间充质干细胞（MSC）中CXCR4的过表达与二肽基肽酶 - 4抑制剂（Diprotin A）联合使用可增强MSC向缺血心肌的募集和渗透，从而改善心肌梗死（MI）后的心脏功能。用腺病毒载体对雄性大鼠MSC进行基因工程改造，使其共表达CXCR4和增强型绿色荧光蛋白（EGFP）（MSCCXCR4）、仅表达GFP（MSCNull，对照）或靶向CXCR4的siRNA（MSCsiRNA）。在雌性大鼠左冠状动脉前降支（LAD）结扎7天后，用赋形剂（VEH）或二肽基肽酶 - 4抑制剂（DIP）预处理，将细胞片置于梗死的左心室（LV）表面。在细胞片植入28天后，进行超声心动图检查。在LAD结扎7天或细胞片植入28天后摘取心脏进行组织学分析。分析左心室中的二肽基肽酶 - 4（DPP - IV）和基质细胞衍生因子 - 1α（SDF - 1α）。通过细胞核中Y染色体的存在（Ych +）来确定植入效果。还分析了左心室血管密度和细胞凋亡情况。在LAD术后第7天，与赋形剂组相比，二肽基肽酶 - 4抑制剂（DIP）组在放置细胞片前心肌SDF - 1α升高。在细胞片移植后第28天，与MSCNull + VEH组相比，MSCCXCR4 + VEH组中Ych +的数量增加，并且在MSCCXCR4 + DIP处理组中进一步增加。这种增强的反应与心外膜两侧血管生成增加以及左心室功能改善相关。基因修饰的MSCCXCR4贴片与二肽基肽酶 - 4抑制剂（DIP）预处理相结合可抑制心肌缺血诱导的细胞凋亡，促进组织血管生成，并增强细胞植入，从而改善心肌梗死后左心室的机械功能。
Zhang D, Huang W, Dai B, Zhao T, Ashraf A, Millard RW, Ashraf M, Wang Y. Genetically manipulated progenitor cell sheet with diprotin A improves myocardial function and repair of infarcted hearts. Am J Physiol Heart Circ Physiol 299: H1339-H1347, 2010. First published August 27, 2010; doi:10.1152/ajpheart.00592.2010.-We postulated that the combination of overexpression of CXCR4 in mesenchymal stem cells (MSC) with diprotin A would enhance MSC recruitment and penetration into ischemic myocardium, leading to an improvement in heart function after myocardial infarction (MI). Male rat MSC were genetically engineered with adenoviral vectors coexpressing CXCR4 and enhanced green fluorescent protein (EGFP) (MSCCXCR4), GFP alone (MSCNull, control), or siRNA-targeted CXCR4 (MSCsiRNA). Cell sheets were applied over the surface of infarcted left ventricle (LV) in female rats 7 days after ligation of the left anterior descending coronary artery (LAD) pretreated with either vehicle (VEH) or diprotin A (DIP). At 28 days after cell sheet implantation, echocardiography was performed. Hearts were harvested for histological analysis 7 days after LAD ligation or 28 days after cell sheet implantation. DPP-IV and stroma-derived factor-1 alpha (SDF-1 alpha) in the LV were analyzed. Efficacy of engraftment was determined by the presence of Y chromosome in nuclei (Ych+). LV blood vessel density and apoptosis were also analyzed. Myocardial SDF-1 alpha was elevated before placement of the cell sheet in the DIP group compared with vehicle group on day 7 after LAD. On day 28 after cell sheet transplantation, the number of Ych+ was increased in the MSCCXCR4 + VEH group compared with the MSCNull + VEH group and further increased in the MSCCXCR4 + DIP treated group. This enhanced response was associated with increased angiogenesis in both sides of epicardium and improvement of LV function. Combination of gene-manipulated MSCCXCR4 patch with DIP pretreatment inhibits myocardial ischemia-induced apoptosis, promotes tissue angiogenesis, and enhances cell engraftment, leading to improved LV mechanical function after MI.