Cloche/Npas4l is a pro-regenerative platelet factor during zebrafish heart regeneration. Hou et al.

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 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 npas4l was dynamically expressed in platelets after heart injury and regulated robust interactions between platelets-CMs or -ECs. Decreasing platelets impaired CM/EC proliferation, and over-expression 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 regulated a panel of ligands expression including bmp6 in platelets to fine-tune CM proliferation and heart regeneration. Therefore, this work demonstrates a platelet Npas4l signaling and presents mechanisms on how platelets modulate CM/EC proliferation via ligand-receptor network during zebrafish heart regeneration.