Liu Huahua, Dong Jinling, Liu Shuang, Luo Yuru, Fang Yuan, Su Hongyu, Xue Weihao, Zhou Rui, Huang Wenjun, Lai Baochang, Xiong Ying, Wang Shuangshuang, Liang Lingli, Wang Zhen, Zhang Donghong, Wu Lianpin, Zhang Yanmin, Zhou Bin, Shyy John Y-J, Yuan Zuyi, Wang Yidong
Department of Cardiology, First Affiliated Hospital; Cardiometabolic Innovation Center of Ministry of Education, Xi'an Jiaotong University, Xi'an, China.
The Institute of Cardiovascular Sciences, School of Basic Medical Sciences; Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, China.
Theranostics. 2025 May 25;15(13):6313-6328. doi: 10.7150/thno.110297. eCollection 2025.
Improving heart regeneration through reactivating cardiomyocyte proliferation holds a great potential for repairing diseased hearts. We recently reported that LSD1-dependent epigenetic repression of Cend1 transcription is prerequisite for cardiomyocyte proliferation and mouse heart development. This study interrogates the potential role of this LSD1-CEND1 axis in heart regeneration and repair. The cardiomyocyte-specific Lsd1 knockout or overexpression mice, Cend1 null mice and cardiomyocyte-specific Cend1 overexpression mice were used to determine the role of LSD1-CEND1 axis in heart regeneration after experimental injuries. Neonatal and adult mice were subjected to apical resection or left anterior descending coronary artery ligation, respectively, to establish cardiac injury models. Echocardiography and Masson staining were employed to assess cardiac function and histopathology, respectively. The molecular changes were determined using RNA sequencing, quantitative RT-PCR, Western blotting and immunostaining. Cardiomyocyte-specific deletion impeded neonatal heart regeneration, while overexpression of Lsd1 had the opposite effect. RNA sequencing revealed that Cend1, a crucial suppressor of cardiomyocyte cycling, was the most significantly elevated gene induced by Lsd1 loss during heart regeneration. Cardiomyocyte-specific Cend1 overexpression hindered neonatal heart regeneration, while Cend1 loss in nullizygous mice had the opposite effect. Cend1 deletion resulted in gene expression alterations associated with enhanced cardiomyocyte proliferation, neovascularization, and macrophage activation. Furthermore, the cardiac regeneration defect caused by Lsd1 loss was not observed when experiments were performed with mice that were nullizyogus for Cend1. Moreover, we found that either Lsd1 overexpression or Cend1 deletion could promote heart regeneration and repair, and improve cardiac function following experimental myocardial infraction in adult mice. Our results demonstrate that LSD1-dependent suppression of CEND1 is crucial for heart regeneration in neonatal and adult mice after experimental injury. These findings suggest LSD1 activation and CEND1 inhibition as promising therapeutic strategies to enhance endogenous cardiac repair in humans.
通过重新激活心肌细胞增殖来改善心脏再生，对于修复患病心脏具有巨大潜力。我们最近报道，LSD1依赖的Cend1转录表观遗传抑制是心肌细胞增殖和小鼠心脏发育的先决条件。本研究探讨了这个LSD1-CEND1轴在心脏再生和修复中的潜在作用。使用心肌细胞特异性Lsd1基因敲除或过表达小鼠、Cend1基因敲除小鼠和心肌细胞特异性Cend1过表达小鼠，来确定LSD1-CEND1轴在实验性损伤后心脏再生中的作用。分别对新生小鼠和成年小鼠进行心尖切除或左前降支冠状动脉结扎，以建立心脏损伤模型。采用超声心动图和Masson染色分别评估心脏功能和组织病理学。使用RNA测序、定量RT-PCR、蛋白质免疫印迹和免疫染色来确定分子变化。心肌细胞特异性缺失阻碍了新生心脏的再生，而Lsd1过表达则有相反的效果。RNA测序显示，Cend1是心肌细胞周期的关键抑制因子，是心脏再生过程中因Lsd1缺失而诱导上调最显著的基因。心肌细胞特异性Cend1过表达阻碍了新生心脏的再生，而纯合子小鼠中Cend1缺失则有相反的效果。Cend1缺失导致与增强心肌细胞增殖、新血管形成和巨噬细胞激活相关的基因表达改变。此外，在用Cend1基因敲除的小鼠进行实验时，未观察到因Lsd1缺失导致的心脏再生缺陷。而且，我们发现Lsd1过表达或Cend1缺失均可促进成年小鼠实验性心肌梗死后的心脏再生和修复，并改善心脏功能。我们的结果表明，LSD1依赖的CEND1抑制对于新生和成年小鼠实验性损伤后的心脏再生至关重要。这些发现提示，激活LSD1和抑制CEND1有望成为增强人类内源性心脏修复的治疗策略。
