Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, P. R. China.
Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P. R. China.
Theranostics. 2024 Jun 24;14(10):3927-3944. doi: 10.7150/thno.96460. eCollection 2024.
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. 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. 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. 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.
心肌梗死（MI）是一种严重的全球性临床病症，其发病率广泛。成年哺乳动物心脏在受到损伤时生成新心肌细胞（CMs）的能力有限，这仍然是开发有效治疗方法的主要障碍。目前的方法主要集中在通过细胞周期再进入来诱导现有 CMs 的增殖。然而，这种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 CMs 的形成。胞质分裂依赖于核糖体生物发生（Ribo-bio），这是一个由核仁蛋白（Ncl）调节的关键过程。我们的目标是确定一种促进 DNA 合成和胞质分裂的新方法。我们使用了各种技术，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，来评估增殖/细胞周期再进入和 Ribo-bio/胞质分裂的系列信号。超声心动图、共聚焦成像和组织学用于评估心脏功能。分析显示，与对照组相比，MI 小鼠心脏中的 Rb1 水平显著升高，而 circASXL1 水平降低。Rb1 的缺失仅诱导细胞周期再进入，而增强 Ribo-bio 调节剂 Ncl 则导致胞质分裂。在机制上，生物信息学和缺失/获得研究表明，circASXL1/CDK6/Rb1 调节细胞周期再进入。此外，Ribo-Halo、Ribo-disome 和 circRNA 下拉测定表明，circASXL1 通过 Ncl/Ribo-bio 促进胞质分裂。重要的是，脐带间充质干细胞（UMSC-Exo）衍生的外泌体通过促进细胞周期再进入和 Ribo-bio/cytokinesis 的协调信号，能够增强心脏功能。在 UMSC-Exo 中沉默 circASXL1 可减弱这些作用。circASXL1/CDK6/Rb1/细胞周期再进入和 circASXL1/Ncl/Ribo-bio/胞质分裂的系列信号在心脏修复中起着至关重要的作用。UMSC-Exo 通过以 circASXL1 依赖的方式刺激 CM 细胞周期再进入和胞质分裂，有效修复梗死心肌。这项研究为 MI 提供了针对 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。
