BMP signaling promotes zebrafish heart regeneration via alleviation of replication stress

Mohankrishna Dalvoy Vasudevarao, Denise Posadas Pena, Michaela Ihle, Chiara Bongiovanni, Pallab Maity, Dominik Geissler, Hossein Falah Mohammadi, Melanie Rall-Scharpf, Julian Niemann, Mathilda T. M. Mommersteeg, Simone Redaelli, Kathrin Happ, Chi-Chung Wu, Arica Beisaw, Karin Scharffetter-Kochanek, Gabriele D’Uva, Mona Malek Mohammadi, Lisa Wiesmüller, Hartmut Geiger and Gilbert Weidinger ()
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Mohankrishna Dalvoy Vasudevarao: Ulm University
Denise Posadas Pena: Ulm University
Michaela Ihle: Ulm University
Chiara Bongiovanni: University of Bologna
Pallab Maity: Ulm University
Dominik Geissler: Ulm University
Hossein Falah Mohammadi: Ulm University
Melanie Rall-Scharpf: Ulm University
Julian Niemann: Ulm University
Mathilda T. M. Mommersteeg: University of Oxford
Simone Redaelli: University of Zurich
Kathrin Happ: Ulm University
Chi-Chung Wu: Ulm University
Arica Beisaw: Heidelberg University
Karin Scharffetter-Kochanek: Ulm University
Gabriele D’Uva: University of Bologna
Mona Malek Mohammadi: University of Bonn
Lisa Wiesmüller: Ulm University
Hartmut Geiger: Ulm University
Gilbert Weidinger: Ulm University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract In contrast to mammals, adult zebrafish achieve complete heart regeneration via proliferation of cardiomyocytes. Surprisingly, we found that regenerating cardiomyocytes experience DNA replication stress, which represents one reason for declining tissue regeneration during aging in mammals. Pharmacological inhibition of ATM and ATR kinases revealed that DNA damage response signaling is essential for zebrafish heart regeneration. Manipulation of Bone Morphogenetic Protein (BMP)-Smad signaling using transgenics and mutants showed that BMP signaling alleviates cardiomyocyte replication stress. BMP signaling also rescues neonatal mouse cardiomyocytes, human fibroblasts and human hematopoietic stem and progenitor cells (HSPCs) from replication stress. DNA fiber spreading assays indicate that BMP signaling facilitates re-start of replication forks after replication stress-induced stalling. Our results identify the ability to overcome replication stress as key factor for the elevated zebrafish heart regeneration capacity and reveal a conserved role for BMP signaling in promotion of stress-free DNA replication.

Date: 2025
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DOI: 10.1038/s41467-025-56993-6

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