Forman-Rubinsky Rachel, Paul Angela, Feng Wei, Schlegel Brent T, Zuppo Daniel A, Kedziora Katarzyna, Stoltz Donna B, Watkins Simon C, Rajasundaram Dhivyaa, Li Guang, Tsang Michael
Department of Cell Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
Center for Integrative Organ Systems, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
Development. 2025 Oct 15;152(20). doi: 10.1242/dev.204659. Epub 2025 Aug 19.
Cardiac regeneration involves the interplay of complex interactions between many different cell types, including cardiomyocytes. In regeneration, cardiomyocytes undergo dedifferentiation and proliferation to replace lost cells at the injury border. The exact mechanism regulating this process is not completely understood. Here, we report a single nucleus RNA-sequencing profile of the injured zebrafish heart revealing distinct cardiomyocyte populations. These cardiomyocyte populations have diverse functions, including stress response, myofibril assembly, proliferation and contraction. Notably, increased expression of cited4a, a p300/CBP transcriptional coactivator, was detected in the mature contracting cardiomyocytes, but absent from proliferating cardiomyocytes, suggesting it may play a role in maintaining contractile function in a subset of cardiomyocytes. We reasoned that cited4a is induced in heart injury to maintain cardiomyocyte function and therefore cited4a+ populations are restricted from entering the cell cycle. Loss-of-function cited4a mutants were generated and, following ventricular resection, increased cardiomyocyte dedifferentiation and proliferation was observed. Our findings indicate that suppressing cited4a activity in the injured heart expands the pool of cardiomyocytes available for replacing damaged and lost myocardium and could be an approach to promote heart regeneration.
心脏再生涉及包括心肌细胞在内的多种不同细胞类型之间复杂的相互作用。在再生过程中，心肌细胞经历去分化和增殖，以取代损伤边界处丢失的细胞。调节这一过程的确切机制尚未完全了解。在此，我们报告了受伤斑马鱼心脏的单核RNA测序图谱，揭示了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。值得注意的是，在成熟的收缩性心肌细胞中检测到p300/CBP转录共激活因子cited4a的表达增加，但在增殖性心肌细胞中未检测到，这表明它可能在一部分心肌细胞中维持收缩功能方面发挥作用。我们推断，cited4a在心脏损伤时被诱导以维持心肌细胞功能，因此cited4a+群体被限制进入细胞周期。我们生成了功能缺失的cited4a突变体，并在心室切除术后观察到心肌细胞去分化和增殖增加。我们的研究结果表明，抑制受伤心脏中cited4a的活性可扩大可用于替代受损和丢失心肌的心肌细胞库，这可能是促进心脏再生的一种方法。
