Inhibition of TGF-β/Smad3 Signaling Disrupts Cardiomyocyte Cell Cycle Progression and Epithelial-Mesenchymal Transition-Like Response During Ventricle Regeneration

Yuanyuan Peng; Wenyuan Wang; Yunzheng Fang; Haichen Hu; Nannan Chang; Meijun Pang; Ye-Fan Hu; Xueyu Li; Han Long; Jing-Wei Xiong; Ruilin Zhang

doi:10.3389/fcell.2021.632372

Inhibition of TGF-β/Smad3 Signaling Disrupts Cardiomyocyte Cell Cycle Progression and Epithelial-Mesenchymal Transition-Like Response During Ventricle Regeneration

Front Cell Dev Biol. 2021 Mar 16:9:632372. doi: 10.3389/fcell.2021.632372. eCollection 2021.

Authors

Yuanyuan Peng¹, Wenyuan Wang¹, Yunzheng Fang¹, Haichen Hu², Nannan Chang³, Meijun Pang³, Ye-Fan Hu^{1

4

5}, Xueyu Li¹, Han Long¹, Jing-Wei Xiong³, Ruilin Zhang⁶

Affiliations

¹ School of Life Sciences, Fudan University, Shanghai, China.
² Shanghai Medical College, Fudan University, Shanghai, China.
³ Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.
⁴ Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.
⁵ School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.
⁶ School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Abstract

Unlike mammals, zebrafish can regenerate injured hearts even in the adult stage. Cardiac regeneration requires the coordination of cardiomyocyte (CM) proliferation and migration. The TGF-β/Smad3 signaling pathway has been implicated in cardiac regeneration, but the molecular mechanisms by which this pathway regulates CM proliferation and migration have not been fully illustrated. Here, we investigated the function of TGF-β/Smad3 signaling in a zebrafish model of ventricular ablation. Multiple components of this pathway were upregulated/activated after injury. Utilizing a specific inhibitor of Smad3, we detected an increased ratio of unrecovered hearts. Transcriptomic analysis suggested that the TGF-β/Smad3 signaling pathway could affect CM proliferation and migration. Further analysis demonstrated that the CM cell cycle was disrupted and the epithelial-mesenchymal transition (EMT)-like response was impaired, which limited cardiac regeneration. Altogether, our study reveals an important function of TGF-β/Smad3 signaling in CM cell cycle progression and EMT process during zebrafish ventricle regeneration.

Keywords: EMT-like response; Smad3; TGF-β; cell cycle; ventricle regeneration.