Tudor-SN promotes cardiomyocyte proliferation and neonatal heart regeneration through regulating the phosphorylation of YAP.

IF 8.2 2区生物学 Q1 CELL BIOLOGY Cell Communication and Signaling Pub Date : 2024-06-28 DOI:10.1186/s12964-024-01715-6

Chao Su, Jinzheng Ma, Xuyang Yao, Wei Hao, Shihu Gan, Yixiang Gao, Jinlong He, Yuanyuan Ren, Xingjie Gao, Yi Zhu, Jie Yang, Minxin Wei

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Abstract

Background: The neonatal mammalian heart exhibits considerable regenerative potential following injury through cardiomyocyte proliferation, whereas mature cardiomyocytes withdraw from the cell cycle and lose regenerative capacities. Therefore, investigating the mechanisms underlying neonatal cardiomyocyte proliferation and regeneration is crucial for unlocking the regenerative potential of adult mammalian heart to repair damage and restore contractile function following myocardial injury.

Methods: The Tudor staphylococcal nuclease (Tudor-SN) transgenic (TG) or cardiomyocyte-specific knockout mice (Myh6-Tudor-SN ^-/-) were generated to investigate the role of Tudor-SN in cardiomyocyte proliferation and heart regeneration following apical resection (AR) surgery. Primary cardiomyocytes isolated from neonatal mice were used to assess the influence of Tudor-SN on cardiomyocyte proliferation in vitro. Affinity purification and mass spectrometry were employed to elucidate the underlying mechanism. H9c2 cells and mouse myocardia with either overexpression or knockout of Tudor-SN were utilized to assess its impact on the phosphorylation of Yes-associated protein (YAP), both in vitro and in vivo.

Results: We previously identified Tudor-SN as a cell cycle regulator that is highly expressed in neonatal mice myocardia but downregulated in adults. Our present study demonstrates that sustained expression of Tudor-SN promotes and prolongs the proliferation of neonatal cardiomyocytes, improves cardiac function, and enhances the ability to repair the left ventricular apex resection in neonatal mice. Consistently, cardiomyocyte-specific knockout of Tudor-SN impairs cardiac function and retards recovery after injury. Tudor-SN associates with YAP, which plays important roles in heart development and regeneration, inhibiting phosphorylation at Ser 127 and Ser 397 residues by preventing the association between Large Tumor Suppressor 1 (LATS1) and YAP, correspondingly maintaining stability and promoting nuclear translocation of YAP to enhance the proliferation-related genes transcription.

Conclusion: Tudor-SN regulates the phosphorylation of YAP, consequently enhancing and prolonging neonatal cardiomyocyte proliferation under physiological conditions and promoting neonatal heart regeneration after injury.

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Tudor-SN 通过调节 YAP 的磷酸化促进心肌细胞增殖和新生儿心脏再生。

背景：新生哺乳动物心脏在损伤后通过心肌细胞增殖表现出相当大的再生潜力，而成熟心肌细胞则退出细胞周期并丧失再生能力。因此，研究新生儿心肌细胞增殖和再生的机制，对于释放成年哺乳动物心脏的再生潜力，修复心肌损伤后的损伤和恢复收缩功能至关重要：方法：为了研究Tudor-SN在心尖切除术（AR）后心肌细胞增殖和心脏再生中的作用，我们培育了Tudor葡萄球菌核酸酶（Tudor-SN）转基因小鼠（TG）或心肌细胞特异性基因敲除小鼠（Myh6-Tudor-SN -/-）。从新生小鼠体内分离出的原代心肌细胞被用来评估 Tudor-SN 对体外心肌细胞增殖的影响。亲和纯化和质谱分析被用来阐明其基本机制。利用过表达或敲除 Tudor-SN 的 H9c2 细胞和小鼠心肌来评估其在体外和体内对是相关蛋白（YAP）磷酸化的影响：结果：我们之前发现 Tudor-SN 是一种细胞周期调节因子，它在新生小鼠心肌中高表达，但在成年小鼠心肌中则下调。本研究表明，Tudor-SN 的持续表达可促进和延长新生小鼠心肌细胞的增殖，改善心脏功能，并增强新生小鼠修复左室心尖切除的能力。同样，心肌细胞特异性敲除 Tudor-SN 会损害心脏功能并延缓损伤后的恢复。Tudor-SN与在心脏发育和再生过程中发挥重要作用的YAP结合，通过阻止大肿瘤抑制因子1（LATS1）与YAP的结合，抑制YAP在Ser 127和Ser 397残基上的磷酸化，相应地维持YAP的稳定性并促进其核转位，从而增强增殖相关基因的转录：结论：Tudor-SN能调节YAP的磷酸化，从而增强和延长新生儿心肌细胞在生理条件下的增殖，促进新生儿心脏损伤后的再生。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.