Cloche/Npas4l is a pro-regenerative platelet factor during zebrafish heart regeneration

Junjie Hou1, Yabing Song2, Chenglu Xiao3

  • 1School of Basic Medical Sciences, The Second Affiliated Hospital, Institute of Biomedical Innovation, The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.

Developmental Cell
|July 2, 2025
PubMed

Zebrafish has full capacity of heart regeneration, but little is known about how blood cells, especially platelets, are involved in this regenerative process. Here, we report that cloche/npas4l is a pro-regenerative platelet factor for heart regeneration. We found that haploinsufficiency of npas4l disrupted cardiomyocyte (CM) and endothelial cell (EC) proliferation and heart regeneration after injury. A single-cell transcriptomic atlas identified that npas4l was dynamically expressed in platelets after heart injury and controlled robust interactions between platelet-CMs or -ECs. Decreasing platelets impaired CM/EC proliferation, and overexpression of npas4l in platelets sufficiently induced CM/EC proliferation in uninjured hearts, as well as rescued CM/EC proliferation defects in cloche mutants. Mechanistically, Npas4l positively controlled a panel of ligand expression, including bmp6 in platelets, to fine-tune CM proliferation and heart regeneration. Therefore, this work demonstrates platelet Npas4l signaling and presents mechanisms on how platelets modulate CM/EC proliferation via ligand-receptor network during zebrafish heart regeneration.

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