Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts.
Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts.
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DOI：
10.1038/nature11317
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发表时间：
2012-09-13
期刊：
影响因子：
64.8
通讯作者：
Laflamme, Michael A.
中科院分区：
文献类型：
--
作者：
Shiba, Yuji;Fernandes, Sarah;Zhu, Wei-Zhong;Filice, Dominic;Muskheli, Veronica;Kim, Jonathan;Palpant, Nathan J.;Gantz, Jay;Moyes, Kara White;Reinecke, Hans;Van Biber, Benjamin;Dardas, Todd;Mignone, John L.;Izawa, Atsushi;Hanna, Ramy;Viswanathan, Mohan;Gold, Joseph D.;Kotlikoff, Michael I.;Sarvazyan, Narine;Kay, Matthew W.;Murry, Charles E.;Laflamme, Michael A.
小鼠和大鼠的移植研究表明，人胚胎干细胞衍生的心肌细胞（hESC-CMs）可以改善梗死心脏的功能，但与其体内电生理行为相关的两个关键问题尚未解决。首先，hESC-CM移植到受损心脏后心律失常的风险尚未确定。其次，hESC-CM在受损心脏中的机电整合尚未得到证实，因此尚不清楚这些细胞是否通过添加新的力产生单位直接改善收缩功能。在这里，我们使用豚鼠模型来显示hESC-CM移植物在损伤的心脏中防止心律失常，并且可以与宿主肌肉同步收缩。用hESC-CM移植物损伤的心脏显示出改善的机械功能和显著降低的自发性和诱导性室性心动过速（VT）的发生率。为了评估hESC-CM移植物在体内的活性，我们移植了表达遗传编码的钙传感器GCaMP 3的hESC-CM。通过将GCaMP 3荧光信号与宿主ECG相关联，我们发现未受损心脏中的移植物具有一致的1：1宿主-移植物偶联。受损心脏中的移植物更加异质，通常包括偶联和非偶联区域。因此，人心肌移植物符合真正心脏再生的生理标准，为持续开发用于机械和电修复的基于hESC的心脏疗法提供支持。
Transplantation studies in mice and rats have shown that human embryonic stem cell-derived cardiomyocytes (hESC-CMs) can improve the function of infarcted hearts, but two critical issues related to their electrophysiological behavior in vivo remain unresolved. First, the risk of arrhythmias following hESC-CM transplantation in injured hearts has not been determined. Second, the electromechanical integration of hESC-CMs in injured hearts has not been demonstrated, so it is unclear if these cells improve contractile function directly through addition of new force-generating units. Here we use a guinea pig model to show hESC-CM grafts in injured hearts protect against arrhythmias and can contract synchronously with host muscle. Injured hearts with hESC-CM grafts show improved mechanical function and a significantly reduced incidence of both spontaneous and induced ventricular tachycardia (VT). To assess the activity of hESC-CM grafts in vivo, we transplanted hESC-CMs expressing the genetically-encoded calcium sensor, GCaMP3. By correlating the GCaMP3 fluorescent signal with the host ECG, we found that grafts in uninjured hearts have consistent 1:1 host-graft coupling. Grafts in injured hearts are more heterogeneous and typically include both coupled and uncoupled regions. Thus, human myocardial grafts meet physiological criteria for true heart regeneration, providing support for the continued development of hESC-based cardiac therapies for both mechanical and electrical repair.
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DOI：
10.1016/j.bbrc.2004.06.045
发表时间：
2004-07-30
影响因子：
3.1
作者：
Kolega, J
通讯作者：
Kolega, J
影响因子：
37.8
作者：
Mandel Y;Weissman A;Schick R;Barad L;Novak A;Meiry G;Goldberg S;Lorber A;Rosen MR;Itskovitz-Eldor J;Binah O
通讯作者：
Binah O
影响因子：
46.9
作者：
Hockemeyer, Dirk;Soldner, Frank;Beard, Caroline;Gao, Qing;Mitalipova, Maisam;DeKelver, Russell C.;Katibah, George E.;Amora, Ranier;Boydston, Elizabeth A.;Zeitler, Bryan;Meng, Xiangdong;Miller, Jeffrey C.;Zhang, Lei;Rebar, Edward J.;Gregory, Philip D.;Urnov, Fyodor D.;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
影响因子：
6
作者：
Laflamme, MA;Gold, J;Murry, CE
通讯作者：
Murry, CE
影响因子：
5.5
作者：
Fedorov, Vadim V.;Lozinsky, Ilya T.;Efimov, Igor R.
通讯作者：
Efimov, Igor R.