Forman-Rubinsky Rachel, Feng Wei, Schlegel Brent T, Paul Angela, Zuppo Daniel, Kedziora Katarzyna, Stoltz Donna, Watkins Simon, Rajasundaram Dhivyaa, Li Guang, Tsang Michael
Department of Cell Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA.
Center for Integrative Organ Systems, University of Pittsburgh, School of Medicine, Pittsburgh, PA.
bioRxiv. 2024 Dec 9:2024.12.05.626917. doi: 10.1101/2024.12.05.626917.
Cardiac regeneration involves the interplay of complex interactions between many different cell types, including cardiomyocytes. The exact mechanism that enables cardiomyocytes to undergo dedifferentiation and proliferation to replace lost cells has been intensely studied. Here we report a single nuclear RNA sequencing profile of the injured zebrafish heart and identify distinct cardiomyocyte populations in the injured heart. These cardiomyocyte populations have diverse functions, including stress response, myofibril assembly, proliferation and contraction. The contracting cardiomyocyte population also involves the activation of maturation pathways as an early response to injury. This intriguing finding suggests that constant maintenance of a distinctive terminally differentiated cardiomyocyte population is important for cardiac function during regeneration. To test this hypothesis, we determined that a p300/CBP transcriptional coactivator, is induced after injury in the mature cardiomyocyte population. Moreover, loss-of- mutants presented increased dedifferentiation, proliferation and accelerated heart regeneration. Thus, suppressing cardiomyocyte maturation pathway activity in injured hearts could be an approach to promote heart regeneration.
心脏再生涉及多种不同细胞类型（包括心肌细胞）之间复杂的相互作用。使心肌细胞能够去分化并增殖以替代丢失细胞的确切机制已得到深入研究。在此，我们报告了受伤斑马鱼心脏的单核RNA测序图谱，并鉴定出受伤心脏中不同的心肌细胞群体。这些心肌细胞群体具有多种功能，包括应激反应、肌原纤维组装、增殖和收缩。收缩性心肌细胞群体还涉及成熟途径的激活，作为对损伤的早期反应。这一有趣的发现表明，在再生过程中持续维持独特的终末分化心肌细胞群体对心脏功能很重要。为了验证这一假设，我们确定了一种p300/CBP转录共激活因子在成熟心肌细胞群体受伤后被诱导。此外，该因子缺失的突变体表现出去分化增加、增殖加快以及心脏再生加速。因此，抑制受伤心脏中的心 肌细胞成熟途径活性可能是促进心脏再生的一种方法。
