Embryonic stem cell therapy of heart failure in genetic cardiomyopathy.
Embryonic stem cell therapy of heart failure in genetic cardiomyopathy.
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DOI：
10.1634/stemcells.2008-0187
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发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
Terzic A
中科院分区：
文献类型：
--
作者：
Yamada S;Nelson TJ;Crespo-Diaz RJ;Perez-Terzic C;Liu XK;Miki T;Seino S;Behfar A;Terzic A
非缺血性心肌病的致病原因日益得到解决，但缺乏针对这些常见遗传性心力衰竭的修复疗法。一个典型的例子是人类扩张型心肌病 10（CMD10；Online Mendelian Inheritance in Man #608569），这是一种传统疗法难以治愈的进行性器官功能障碍综合征，与心脏 ATP 敏感 K+ (KATP) 通道亚基的突变有关。胚胎干细胞疗法在缺血性心脏病中显示出益处，但这种同种异体再生细胞来源的修复能力尚未在遗传性心肌病中得到测试。在这里，在缺乏功能性 KATP 通道的 Kir6.2 敲除模型中，我们在压力超载的压力下重现了 CMD10 的基因-环境底物。再现了人类恶性心力衰竭表型的显着特征，包括收缩力受损、心室扩张和生存率低。胚胎干细胞通过心外膜途径递送至心肌病应激的 Kir6.2 缺失突变体的左心室壁。在治疗 1 个月时，每颗心脏移植 200,000 个细胞，实现了收缩功能障碍和电同步的无畸胎瘤逆转，并停止了适应不良的重塑，从而预防了终末期器官衰竭。使用 lacZ 报告基因转基因追踪移植到宿主心脏中的干细胞。除了形成对 Kir6.2 呈阳性的心脏组织外，移植还诱导细胞周期激活和纤维化区域减半，使肌肉重建的心脏内的肌节和间隙连接组织正常化。干细胞治疗诱导的全身功能改善转化为耐力增强、无全身水肿，并有利于整体生存。因此，胚胎干细胞实现了非缺血性遗传性心肌病的功能修复，扩大了遗传性心力衰竭的治疗适应症。
Pathogenic causes underlying nonischemic cardiomyopathies are increasingly being resolved, yet repair therapies for these commonly heritable forms of heart failure are lacking. A case in point is human dilated cardiomyopathy 10 (CMD10; Online Mendelian Inheritance in Man #608569), a progressive organ dysfunction syndrome refractory to conventional therapies and linked to mutations in cardiac ATP-sensitive K+ (KATP) channel sub-units. Embryonic stem cell therapy demonstrates benefit in ischemic heart disease, but the reparative capacity of this allogeneic regenerative cell source has not been tested in inherited cardiomyopathy. Here, in a Kir6.2-knockout model lacking functional KATP channels, we recapitulated under the imposed stress of pressure overload the gene-environment substrate of CMD10. Salient features of the human malignant heart failure phenotype were reproduced, including compromised contractility, ventricular dilatation, and poor survival. Embryonic stem cells were delivered through the epicardial route into the left ventricular wall of cardiomyopathic stressed Kir6.2-null mutants. At 1 month of therapy, transplantation of 200,000 cells per heart achieved teratoma-free reversal of systolic dysfunction and electrical synchronization and halted maladaptive remodeling, thereby preventing end-stage organ failure. Tracked using the lacZ reporter transgene, stem cells engrafted into host heart. Beyond formation of cardiac tissue positive for Kir6.2, transplantation induced cell cycle activation and halved fibrotic zones, normalizing sarcomeric and gap junction organization within remuscularized hearts. Improved systemic function induced by stem cell therapy translated into increased stamina, absence of anasarca, and benefit to overall survivorship. Embryonic stem cells thus achieve functional repair in nonischemic genetic cardiomyopathy, expanding indications to the therapy of heritable heart failure.
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DOI：
10.1084/jem.20061916
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Behfar A;Perez-Terzic C;Faustino RS;Arrell DK;Hodgson DM;Yamada S;Puceat M;Niederländer N;Alekseev AE;Zingman LV;Terzic A
通讯作者：
Terzic A
影响因子：
64.8
作者：
Anversa, P;Nadal-Ginard, B
通讯作者：
Nadal-Ginard, B
影响因子：
5.2
作者：
Arrell, D. Kent;Niederlaender, Nicolas J.;Terzic, Andre
通讯作者：
Terzic, Andre
影响因子：
7.7
作者：
Kane, GC;Behfar, A;Terzic, A
通讯作者：
Terzic, A
影响因子：
82.9
作者：
Fändrich, F;Lin, XB;Binas, B
通讯作者：
Binas, B