理由：心肌梗死 (MI) 是一种严重的全球性临床疾病，普遍存在。成年哺乳动物心脏因损伤而产生新心肌细胞（CM）的能力有限，这仍然是开发有效疗法的主要障碍。目前的方法侧重于通过细胞周期重入诱导现有 CM 的增殖。然而，该方法主要提高细胞周期蛋白依赖性激酶 6 (CDK6) 和 DNA 含量，缺乏适当的胞质分裂，导致功能失调的双核 CM 的形成。细胞分裂依赖于核糖体生物发生 (Ribo-bio)，这是一个由核仁素 (Ncl) 调节的关键过程。我们的目标是找到一种促进 DNA 合成和胞质分裂的新方法。方法：采用多种技术，包括 RNA/蛋白质测序分析、Ribo-Halo、Ribo-disome、流式细胞术和心脏特异性肿瘤抑制因子视网膜母细胞瘤-1 (Rb1) 敲除小鼠，评估增殖/增殖的一系列信号传导。细胞周期再进入和核糖生物/细胞分裂。利用超声心动图、共聚焦成像和组织学来评估心脏功能。结果：分析显示，与对照小鼠相比，MI 小鼠心脏中 Rb1 水平显着升高，但 circASXL1 水平降低。 Rb1 的缺失仅诱导细胞周期重入，而 Ribo-bio 调节剂 Ncl 的增强则导致胞质分裂。机械方面，生物信息学和损失/增益研究发现 circASXL1/CDK6/Rb1 调节细胞周期折返。此外，Ribo-Halo、Ribo-disome 和 circRNA Pull-down 检测表明 circASXL1 通过 Ncl/Ribo-bio 促进胞质分裂。重要的是，源自脐带间充质干细胞（UMSC-Exo）的外泌体能够通过促进细胞周期折返和 Ribo-bio/细胞分裂的协调信号传导来增强心脏功能。通过沉默 UMSC-Exo 中的 circASXL1 可以减弱这些影响。结论：circASXL1/CDK6/Rb1/细胞周期折返和circASXL1/Ncl/Ribo-bio/细胞分裂的一系列信号在心脏修复中发挥着至关重要的作用。 UMSC-Exo 通过以 circASXL1 依赖性方式刺激 CM 细胞周期折返和胞质分裂，有效修复梗塞心肌。这项研究提供了针对 MI 的 circASXL1 信号网络的创新治疗策略，并为增强心脏修复提供了潜在途径。© 作者。

Rationale: Myocardial infarction (MI) is a severe global clinical condition with widespread prevalence. The adult mammalian heart's limited capacity to generate new cardiomyocytes (CMs) in response to injury remains a primary obstacle in developing effective therapies. Current approaches focus on inducing the proliferation of existing CMs through cell-cycle reentry. However, this method primarily elevates cyclin dependent kinase 6 (CDK6) and DNA content, lacking proper cytokinesis and resulting in the formation of dysfunctional binucleated CMs. Cytokinesis is dependent on ribosome biogenesis (Ribo-bio), a crucial process modulated by nucleolin (Ncl). Our objective was to identify a novel approach that promotes both DNA synthesis and cytokinesis. Methods: Various techniques, including RNA/protein-sequencing analysis, Ribo-Halo, Ribo-disome, flow cytometry, and cardiac-specific tumor-suppressor retinoblastoma-1 (Rb1) knockout mice, were employed to assess the series signaling of proliferation/cell-cycle reentry and Ribo-bio/cytokinesis. Echocardiography, confocal imaging, and histology were utilized to evaluate cardiac function. Results: Analysis revealed significantly elevated levels of Rb1, bur decreased levels of circASXL1 in the hearts of MI mice compared to control mice. Deletion of Rb1 induces solely cell-cycle reentry, while augmenting the Ribo-bio modulator Ncl leads to cytokinesis. Mechanically, bioinformatics and the loss/gain studies uncovered that circASXL1/CDK6/Rb1 regulates cell-cycle reentry. Moreover, Ribo-Halo, Ribo-disome and circRNA pull-down assays demonstrated that circASXL1 promotes cytokinesis through Ncl/Ribo-bio. Importantly, exosomes derived from umbilical cord mesenchymal stem cells (UMSC-Exo) had the ability to enhance cardiac function by facilitating the coordinated signaling of cell-cycle reentry and Ribo-bio/cytokinesis. These effects were attenuated by silencing circASXL1 in UMSC-Exo. Conclusion: The series signaling of circASXL1/CDK6/Rb1/cell-cycle reentry and circASXL1/Ncl/Ribo-bio/cytokinesis plays a crucial role in cardiac repair. UMSC-Exo effectively repairs infarcted myocardium by stimulating CM cell-cycle reentry and cytokinesis in a circASXL1-dependent manner. This study provides innovative therapeutic strategies targeting the circASXL1 signaling network for MI and offering potential avenues for enhanced cardiac repair.© The author(s).