Beisaw Arica, Wu Chi-Chung
Institute of Experimental Cardiology, Heidelberg University, Heidelberg, Germany.
European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
Dev Dyn. 2024 Jan;253(1):8-27. doi: 10.1002/dvdy.557. Epub 2022 Dec 21.
Cardiovascular disease is a leading cause of death worldwide. Due to the limited proliferative and regenerative capacity of adult cardiomyocytes, the lost myocardium is not replenished efficiently and is replaced by a fibrotic scar, which eventually leads to heart failure. Current therapies to cure or delay the progression of heart failure are limited; hence, there is a pressing need for regenerative approaches to support the failing heart. Cardiomyocytes undergo a series of transcriptional, structural, and metabolic changes after birth (collectively termed maturation), which is critical for their contractile function but limits the regenerative capacity of the heart. In regenerative organisms, cardiomyocytes revert from their terminally differentiated state into a less mature state (ie, dedifferentiation) to allow for proliferation and regeneration to occur. Importantly, stimulating adult cardiomyocyte dedifferentiation has been shown to promote morphological and functional improvement after myocardial infarction, further highlighting the importance of cardiomyocyte dedifferentiation in heart regeneration. Here, we review several hallmarks of cardiomyocyte maturation, and summarize how their reversal facilitates cardiomyocyte proliferation and heart regeneration. A detailed understanding of how cardiomyocyte dedifferentiation is regulated will provide insights into therapeutic options to promote cardiomyocyte de-maturation and proliferation, and ultimately heart regeneration in mammals.
心血管疾病是全球主要的死亡原因。由于成年心肌细胞的增殖和再生能力有限，受损的心肌无法有效补充，而是被纤维化瘢痕取代，最终导致心力衰竭。目前治疗或延缓心力衰竭进展的方法有限；因此，迫切需要采用再生方法来支持衰竭心脏。心肌细胞在出生后会经历一系列转录、结构和代谢变化（统称为成熟），这对其收缩功能至关重要，但限制了心脏的再生能力。在可再生的生物体中，心肌细胞从终末分化状态恢复到不太成熟的状态（即去分化），从而实现增殖和再生。重要的是，刺激成年心肌细胞去分化已被证明可促进心肌梗死后的形态和功能改善，进一步凸显了心肌细胞去分化在心脏再生中的重要性。在此，我们综述了心肌细胞成熟的几个特征，并总结了它们的逆转如何促进心肌细胞增殖和心脏再生。深入了解心肌细胞去分化的调控机制将为促进心肌细胞去成熟和增殖以及最终实现哺乳动物心脏再生的治疗选择提供思路。
