Myocardial infarction is a leading global cause of death and disability. Unlike the adult mammalian heart, which responds to injury with permanent scarring and loss of function, the Zebrafish heart possesses remarkable regenerative ability. Following resection of up to 20% of the ventricle, Zebrafish fully regenerate lost myocardium through dedifferentiation and proliferation of preexisting cardiomyocytes, ultimately restoring normal cardiac structure and function. Understanding these unique regenerative mechanisms in Zebrafish offers critical insights and potential therapeutic strategies for promoting heart regeneration in patients after myocardial infarction.

After cardiac injury, Zebrafish mount a highly coordinated regenerative response over the course of 1–2 months, involving inflammation, epicardial activation, angiogenesis, and cardiomyocyte dedifferentiation and proliferation, ultimately leading to complete structural and functional recovery. While signals from the epicardium, cardiomyocytes, endocardium, and macrophages are known to orchestrate regeneration, the potential role of platelet-derived signals has remained unexplored until now.

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On July 1, 2025, a team led by Prof. Xiong Jing-Wei from the School of Basic Medical Sciences, the Second Affiliated Hospital, and the Institute of Biomedical Innovation at Nanchang University published a study in  Developmental Cell  entitled “Cloche/Npas4l is a pro-regenerative platelet factor during zebrafish heart regeneration”. The work uncovered a previously unknown yet critical role for platelets in cardiac repair, demonstrating that the platelet-derived  Npas4l – Bmp6  signaling axis potently drives cardiomyocyte proliferation and successful heart regeneration in zebrafish.

Cloche/Npas4l  is well-known for its role in the earliest stages of Zebrafish development, where it acts as a pioneer transcription factor regulating the formation of the blood circulation system. A mutation in this gene leads to severe defects, including the absence of most blood and vascular cells and eventual heart failure.

In this new study, researchers found that even heterozygous adult Zebrafish (carrying only one mutant copy) suffered from impaired heart regeneration, with notable drops in cardiomyocyte proliferation and new blood vessel formation.

Using single-cell sequencing, the team traced  npas4l  expression specifically to platelets and red blood cells—a finding confirmed by RT-qPCR and RNAscope. Further experiments with platelet-deficient mutants showed that the absence of platelets stalled the regeneration process, proving that these cells are vital for heart repair.

A key distinction noted in the study is that, unlike mammalian platelets, Zebrafish platelets possess nuclei and can actively regulate gene expression. Using advanced sequencing and analysis techniques, the researchers discovered that  Npas4l  directly controls the expression of  Bmp6 , a platelet factor.  Bmp6  acts as a ligand on the cell surface, triggering the BMP signaling pathway in cardiomyocytes to fuel proliferation and heart regeneration.

In summary, this study reveals that the platelet-derived Npas4l-Bmp6 signaling pathway drives cardiomyocyte proliferation during zebrafish heart regeneration, thereby underscoring platelets' critical role. Furthermore, it identifies other platelet-secreted proteins—such as Hbegfb, Vegfc, and Serpine1—as promising targets for future investigation.

The study's joint first authors are Hou Junjie (Postdoctoral Fellow) and Xiao Chenglu (Researcher), both affiliated with Nanchang University, as well as Song Yabing (PhD student at Tsinghua University, graduated). The work was jointly supervised by corresponding authors Professor Xiong Jing-Wei  (Nanchang University and Peking University School of Future Technology), Dr. Wang Jianbin (School of Life Sciences, Tsinghua University), and Dr. Zhu Xiaojun (Peking University). This research was supported by grants from the National Key R&D Program of China (2023YFA1800600、2018YFA0800501), the National Natural Science Foundation of China (NSFC) (32230032, 31730061,81870198, T2225005), and the National Health Commission (2023ZD0519900). Additionally, first author Dr. Hou Junjie received funding from the Nanchang University School of Basic Medical Sciences Excellent Postdoctoral Fellowship Fund.