Genetically Engineered Mesenchymal Stem Cells Influence Gene Expression in Donor Cardiomyocytes and the Recipient Heart.
Genetically Engineered Mesenchymal Stem Cells Influence Gene Expression in Donor Cardiomyocytes and the Recipient Heart.
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DOI：
10.4172/2157-7633.s1-005
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发表时间：
2012-06
期刊：
影响因子：
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通讯作者：
M. Kearns-Jonker;W. Dai;Mirja Gunthart;Tania I. Fuentes;Hsiao-Yun Yeh;Paul Z. Gerczuk;M. Pera;C. Mummery;R. Kloner
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文献类型：
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作者：
M. Kearns-Jonker;W. Dai;Mirja Gunthart;Tania I. Fuentes;Hsiao-Yun Yeh;Paul Z. Gerczuk;M. Pera;C. Mummery;R. Kloner
目标：人胚胎干细胞衍生的心肌细胞（hESC-CM）或间充质干细胞（MSC）促进梗死后恢复，但使用MSC和hESC-CM的联合治疗的潜在益处尚未被检查。我们的目的是确定基因表达的变化，在供体和宿主来源的细胞，诱导在体内共移植后的心肌细胞和无间充质干细胞表达促生存基因血红素加氧酶1。方法和结果：在慢病毒载体介导的转导后，人MSC被工程化以过表达血红素加氧酶-1（HO-1）。使无胸腺裸大鼠经受心肌梗死并接受单独的hESC-CM、hESC-CM+人MSC、hESC-CM+过表达HO-1的MSC或盐水。真实的时间PCR鉴定基因表达变化。通过血管造影评估心功能。未修饰的MSC加hESC-CM的共移植使CXCR 4、HGF和IGF的表达升高超过单独注射hESC衍生的心肌细胞诱导的水平。在与过表达HO-1的MSC共移植的动物中，这些基因的表达进一步升高。HO-1 MSC + hESC-CM组VEGF、TGF-β、CCL 2、SMAD 7、STAT 3和心肌细胞转录因子的基因表达水平在30天时最高。人CD 31+、CD 34+、isl-1+、NXK2.5和c-kit+转录物升高。啮齿类动物编码NKX2.5、肌钙蛋白T和CD 31的基因升高，细胞周期基因被诱导。射血分数提高了6%到7%。结论：HO-1 MSC + hESC-CM的共同给药增加了人细胞中促存活和血管生成促进基因的表达以及啮齿动物细胞中心脏和内皮细胞标志物的转录，这与移植的hESC-CM和宿主心脏中组织修复的激活一致。
AIMS: Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) or mesenchymal stem cells (MSCs) facilitate post-infarct recovery, but the potential benefit of combination therapy using MSCs and hESC-CMs has not been examined. Our objective was to define the gene expression changes in donor and host-derived cells that are induced in vivo after co-transplantation of cardiomyocytes with and without mesenchymal stem cells expressing the prosurvival gene heme oxygenase 1. METHODS AND RESULTS: Human MSCs were engineered to over-express heme oxygenase-1 (HO-1) following lentiviral vector-mediated transduction. Athymic nude rats were subjected to myocardial infarction and received hESC-CMs alone, hESC-CMs plus human MSCs, hESC-CMs plus MSCs overexpressing HO-1, or saline. Real time PCR identified gene expression changes. Cardiac function was assessed by angiography. Co-transplantation of unmodified MSCs plus hESC-CMs elevated CXCR4, HGF, and IGF expression over levels induced by injection of hESC-derived cardiomyocytes alone. In animals co-transplanted with MSC over-expressing HO-1, the expression of these genes was further elevated. Gene expression levels of VEGF, TGF-β, CCL2, SMAD7, STAT3 and cardiomyocyte transcription factors were highest in the HO-1 MSC plus hESC-CM group at 30 days. Human CD31+, CD34+, isl-1+, NXK2.5 and c-kit+ transcripts were elevated. Rodent genes encoding NKX2.5, troponin T and CD31 were elevated and cell cycle genes were induced. Ejection fraction improved by six to seven percent. CONCLUSIONS: Co-administration of HO-1 MSCs plus hESC-CMs increased expression of pro-survival and angiogenesis-promoting genes in human cells and transcripts of cardiac and endothelial cell markers in rodent cells, consistent with activation of tissue repair in both transplanted hESC-CMs and the host heart.