Jang Jihyun, Bentsen Mette, Bu Jin, Chen Ling, Campos Alexandre Rosa, Looso Mario, Li Deqiang
Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH 43205, USA.
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA.
J Mol Cell Biol. 2025 May 2;16(10). doi: 10.1093/jmcb/mjae044.
Postnatal mammalian cardiomyocytes (CMs) rapidly lose proliferative capacity and exit the cell cycle to undergo further differentiation and maturation. Cell cycle activation has been a major strategy to stimulate postnatal CM proliferation, albeit achieving modest effects. One impediment is that postnatal CMs may need to undergo dedifferentiation before proliferation, if not simultaneously. Here, we report that overexpression of Hdac7 in neonatal mouse CMs results in significant CM dedifferentiation and proliferation. Mechanistically, we show that histone deacetylase 7 (HDAC7)-mediated CM proliferation is contingent on dedifferentiation, which is accomplished by suppressing myocyte enhance factor 2 (MEF2). Hdac7 overexpression in CM shifts the chromatin state from binding with MEF2, which favors the transcriptional program toward differentiation, to binding with AP-1, which favors the transcriptional program toward proliferation. Furthermore, we found that HDAC7 interacts with minichromosome maintenance complex components to initiate cell cycle progression. Our findings reveal that HDAC7 promotes CM proliferation by its dual action on CM dedifferentiation and proliferation, uncovering a potential new strategy for heart regeneration/repair.
出生后的哺乳动物心肌细胞（CMs）迅速丧失增殖能力并退出细胞周期，以进行进一步的分化和成熟。细胞周期激活一直是刺激出生后CM增殖的主要策略，尽管效果有限。一个障碍是，出生后的CMs可能需要在增殖之前经历去分化，即便不是同时进行。在此，我们报告在新生小鼠CMs中过表达Hdac7会导致显著的CM去分化和增殖。从机制上来说，我们表明组蛋白脱乙酰酶7（HDAC7）介导的CM增殖取决于去分化，这是通过抑制肌细胞增强因子2（MEF2）来实现的。CM中Hdac7的过表达将染色质状态从与MEF2结合（这有利于向分化的转录程序）转变为与AP-1结合（这有利于向增殖的转录程序）。此外，我们发现HDAC7与微型染色体维持复合体成分相互作用以启动细胞周期进程。我们的研究结果表明，HDAC7通过其对CM去分化和增殖的双重作用促进CM增殖，揭示了一种潜在的心脏再生/修复新策略。
