Proarrhythmic potential of mesenchymal stem cell transplantation revealed in an in vitro coculture model
Proarrhythmic potential of mesenchymal stem cell transplantation revealed in an in vitro coculture model
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DOI：
10.1161/circulationaha.105.593038
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发表时间：
2006-04-18
期刊：
影响因子：
37.8
通讯作者：
Abraham, R
中科院分区：
文献类型：
--
作者：
Chang, MG;Tung, L;Abraham, R
间充质干细胞（MSCs）是骨髓基质细胞，正处于细胞心肌成形术的第一阶段临床研究。然而，尚未研究MSC移植的电生理效应。虽然心室功能的改善将代表MSC移植的积极结果，但干细胞的局部应用具有产生不均匀性的潜在缺点，所述不均匀性可能使心脏易于发生折返性心律失常。在本研究中，我们使用的MSC和新生大鼠心室肌细胞（NRVM）共培养系统，以探讨潜在的prophemic后果的MSC移植到heart.Methods和结果-人MSC与NRVM共培养的比例为1：99，1：9，1：4和光学映射。我们发现，与对照组相比，共培养的传导速度降低，但动作电位时程（APD（80））不受影响。在含有10%和20%MSC的共培养物（n = 36）中诱导了86%的折返性心律失常，但在对照（n = 7）或仅含有1%MSC的共培养物（n = 4）中未诱导折返性心律失常。免疫染色，蛋白质印迹和染料转移显示存在的功能性间隙连接，涉及MSCs.Conclusions -我们的研究结果表明，混合物的间充质干细胞和NRVMs可以产生一个致瘤底物。再进入的机制可能是由于不可兴奋的MSC与肌细胞的电偶联导致的组织异质性增加。
Background - Mesenchymal stem cells (MSCs) are bone marrow stromal cells that are in phase 1 clinical studies of cellular cardiomyoplasty. However, the electrophysiological effects of MSC transplantation have not been studied. Although improvement of ventricular function would represent a positive outcome of MSC transplantation, focal application of stem cells has the potential downside of creating inhomogeneities that may predispose the heart to reentrant arrhythmias. In the present study we use an MSC and neonatal rat ventricular myocyte (NRVM) coculture system to investigate potential proarrhythmic consequences of MSC transplantation into the heart.Methods and Results - Human MSCs were cocultured with NRVMs in ratios of 1: 99, 1: 9, and 1: 4 and optically mapped. We found that conduction velocity was decreased in cocultures compared with controls, but action potential duration (APD(80)) was not affected. Reentrant arrhythmias were induced in 86% of cocultures containing 10% and 20% MSCs (n = 36) but not in controls ( n = 7) or cocultures containing only 1% MSCs ( n = 4). Immunostaining, Western blot, and dye transfer revealed the presence of functional gap junctions involving MSCs.Conclusions - Our results suggest that mixtures of MSCs and NRVMs can produce an arrhythmogenic substrate. The mechanism of reentry is probably increased tissue heterogeneity resulting from electric coupling of inexcitable MSCs with myocytes.