Inducible cardiomyocyte injury within the atrioventricular conduction system uncovers latent regenerative capacity in mice
Inducible cardiomyocyte injury within the atrioventricular conduction system uncovers latent regenerative capacity in mice
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DOI：
10.1172/jci138637
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发表时间：
2021-10-01
影响因子：
15.9
通讯作者：
Munshi, Nikhil V.
中科院分区：
文献类型：
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作者：
Wang, Lin;Bhakta, Minoti;Munshi, Nikhil V.
心脏传导系统(CCS)确保有规律的收缩功能，其任何组成部分的损伤都可能导致心律失常。虽然所有的心肌细胞(CMS)都起源于共同的祖细胞，但CCS由不同的细胞类型组成，具有独特的功能和发育特性。与出生后继续增殖的心室肌细胞不同，大多数CCS细胞在胎儿发育期间最终退出细胞周期。因此，尽管CCS为出生后的损伤修复提供了一个较差的底物，但其再生能力仍未得到测试。在这里，我们描述了位于房室传导系统(AvCs)内的CMS消融的遗传系统。成年小鼠消融动静脉曲张导致以持续性房室传导缺陷和收缩功能障碍为特征的再生衰竭。相比之下，新生小鼠的AVCs损伤导致这些小鼠的一部分恢复，从而为CCS的可塑性提供了证据。此外，CM的增殖似乎不能完全解释观察到的功能恢复，这表明调控心律失常恢复的机制可能不同于与心脏损伤相关的心脏再生。综上所述，我们预计我们的结果将促进CCS可塑性的进一步机制研究，并使探索节律恢复作为一种替代治疗策略成为可能。
The cardiac conduction system (CCS) ensures regular contractile function, and injury to any of its components can cause cardiac dysrhythmia. Although all cardiomyocytes (CMs) originate from common progenitors, the CCS is composed of biologically distinct cell types with unique functional and developmental characteristics. In contrast to ventricular cardiomyocytes, which continue to proliferate after birth, most CCS cells terminally exit the cell cycle during fetal development. Although the CCS should thus provide a poor substrate for postnatal injury repair, its regenerative capacity remains untested. Here, we describe a genetic system for ablating CMs that reside within the atrioventricular conduction system (AVCS). Adult mouse AVCS ablation resulted in regenerative failure characterized by persistent atrioventricular conduction defects and contractile dysfunction. In contrast, AVCS injury in neonatal mice led to recovery in a subset of these mice, thus providing evidence for CCS plasticity. Furthermore, CM proliferation did not appear to completely account for the observed functional recovery, suggesting that mechanisms regulating recovery from dysrhythmia are likely to be distinct from cardiac regeneration associated with ventricular injury. Taken together, we anticipate that our results will motivate further mechanistic studies of CCS plasticity and enable the exploration of rhythm restoration as an alternative therapeutic strategy.