Wang Yanfang, Wang Xiaoyu, Fang Ji, Chen Xiaoli, Xu Teng, Zhuang Tao, Peng Sheng, Bao Wenzhen, Wu Wenrun, Lu Yushi, Wang Haikun, Tomlinson Brian, Chan Paul, Zhuang Shougang, Zhang Qi, Zhang Lin, Liu Zhongmin, Pi Jingjiang, Zhang Yuzhen, Liu Jie
State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
Department of Cardiology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, 241001, China.
Adv Sci (Weinh). 2025 Mar;12(12):e2412124. doi: 10.1002/advs.202412124. Epub 2025 Feb 3.
The adult mammalian heart has limited regenerative capacity to replace lost tissue after a major injury. Forkhead box P1 (Foxp1) regulates embryonic cardiomyocyte proliferation and heart development. However, whether Foxp1 participates in postnatal-injury cardiomyocyte proliferation and heart regeneration remains unclear. This study demonstrates that Foxp1 is downregulated at border zone cardiomyocytes of both neonatal apical resection and adult myocardial infarction. Analysis of the Single-cell transcriptome database reveals reduced Foxp1 expression in the cardiomyocyte population with high regenerative capacity. Cardiomyocyte-Foxp1 loss-of-function significantly promotes, whereas cardiomyocytes-Foxp1 gain-of-function suppresses cardiomyocyte proliferation. Mechanistically, Foxp1 directly regulates ubiquitin specific peptidase 20 (USP20), a de-ubiquitinase that prevents hypoxia inducible factor 1ɑ (HIF1α) degradation. Thus, Foxp1 regulates HIF1α and downstream heart and neural crest derivatives expressed 1 (Hand1) to control the cardiomyocyte proliferation via metabolic transition from fatty acid oxidation to glycolysis. Finally, cardiac type troponin T2 (cTnT)-promoter-driven adeno-associated virus 9 (AAV9) for Hand1 induction in cardiomyocytes significantly promoted cardiac regeneration and functional recovery. These findings may provide novel molecular strategies to promote heart regeneration and therapeutic interventions for heart failure.
成年哺乳动物心脏在遭受重大损伤后，替换受损组织的再生能力有限。叉头框P1（Foxp1）调节胚胎心肌细胞增殖和心脏发育。然而，Foxp1是否参与出生后损伤后的心肌细胞增殖和心脏再生仍不清楚。本研究表明，在新生小鼠心尖切除和成年心肌梗死的边缘区心肌细胞中，Foxp1表达下调。单细胞转录组数据库分析显示，在具有高再生能力的心肌细胞群体中，Foxp1表达降低。心肌细胞中Foxp1功能缺失显著促进心肌细胞增殖，而Foxp1功能获得则抑制心肌细胞增殖。机制上，Foxp1直接调节泛素特异性肽酶20（USP20），一种去泛素酶，可防止缺氧诱导因子1α（HIF1α）降解。因此，Foxp1通过从脂肪酸氧化到糖酵解的代谢转变来调节HIF1α及其下游的心脏和神经嵴衍生蛋白1（Hand1），从而控制心肌细胞增殖。最后，通过心肌肌钙蛋白T2（cTnT）启动子驱动的腺相关病毒9（AAV9）在心肌细胞中诱导Hand1，显著促进了心脏再生和功能恢复。这些发现可能为促进心脏再生及心力衰竭的治疗干预提供新的分子策略。
