Extracellular vesicle-derived CircWhsc1 promotes cardiomyocyte proliferation and heart repair by activating TRIM59/STAT3/Cyclin B2 pathway

Guoquan Wei; Chuling Li; Xiaoqian Jia; Jingfang Xie; Zhenquan Tang; Ming Jin; Qiqi Chen; Yili Sun; Sisi He; Xinzhong Li; Yanmei Chen; Hao Zheng; Wangjun Liao; Yulin Liao; Jianping Bin; Senlin Huang

Journal of Advanced Research (Nov 2023)

Extracellular vesicle-derived CircWhsc1 promotes cardiomyocyte proliferation and heart repair by activating TRIM59/STAT3/Cyclin B2 pathway

Guoquan Wei,
Chuling Li,
Xiaoqian Jia,
Jingfang Xie,
Zhenquan Tang,
Ming Jin,
Qiqi Chen,
Yili Sun,
Sisi He,
Xinzhong Li,
Yanmei Chen,
Hao Zheng,
Wangjun Liao,
Yulin Liao,
Jianping Bin,
Senlin Huang

Affiliations

Guoquan Wei: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
Chuling Li: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
Xiaoqian Jia: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
Jingfang Xie: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
Zhenquan Tang: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
Ming Jin: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
Qiqi Chen: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
Yili Sun: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
Sisi He: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
Xinzhong Li: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
Yanmei Chen: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
Hao Zheng: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
Wangjun Liao: Department of Oncology, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China
Yulin Liao: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
Jianping Bin: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China; Corresponding authors at: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China.
Senlin Huang: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China; Corresponding authors at: Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China.

Journal volume & issue: Vol. 53
pp. 199 – 218

Abstract

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Introduction: Extracellular vesicles (EVs)-mediated cell-to-cell communication is crucial for hypoxia-induced cell proliferation and tissue repair, but its function in endogenous cardiac regeneration is still unknown. Objectives: Herein, we aimed to determine whether hypoxia-inducible circWhsc1 in endothelial EVs promoted cardiomyocyte (CM) proliferation and cardiac regeneration. Methods: RNA-sequence data was used to identify EV circRNAs that were involved into endogenous cardiac regeneration. Quantitative polymerase chain reactions were conducted to determine circRNA expression in tissue, cells and EVs. Gain- and loss-of-function assays were performed to explore the function of EV-derived circWhsc1 during cardiac regeneration. Western blotting and RNA pulldown assays were used to investigate its underlying mechanism. Results: We found that circWhsc1 was enriched in neonatal mouse hearts, particularly in cardiac ECs, and was further upregulated both in ECs and EC-derived EVs under hypoxic conditions. When cocultured with hypoxia-preconditioned neonatal ECs or their secreted EVs, both neonatal and adult CMs exhibited an increased proliferation rate and G2/M ratio, which could be attenuated by knockdown of circWhsc1 in ECs. In vivo, EC-restricted overexpression of circWhsc1 and EV-mediated delivery of circWhsc1 induced CM proliferation, alleviated cardiac fibrosis and restored cardiac function following myocardial infarction in adult mice. Mechanistic studies revealed that EV-derived circWhsc1 activated TRIM59 by enhancing its phosphorylation, thereby reinforcing the binding of TRIM59 to STAT3, phosphorylating STAT3 and inducing CM proliferation. Conclusion: The current study demonstrated that hypoxia-inducible circWhsc1 in EC-derived EVs induces CM proliferation and heart regeneration. EC-CM communication mediated by EV-derived circWhsc1 might represent a prospective therapeutic target for inducing cardiac repair post-myocardial infarction.

Published in Journal of Advanced Research

ISSN: 2090-1232 (Print); 2090-1224 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Science (General)
Website: http://www.journals.elsevier.com/journal-of-advanced-research/

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