Border-zone cardiomyocytes and macrophages regulate extracellular matrix remodeling to promote cardiomyocyte protrusion during cardiac regeneration

Florian Constanty, Bailin Wu, Ke-Hsuan Wei, I-Ting Lin, Julia Dallmann, Stefan Guenther, Till Lautenschlaeger, Rashmi Priya, Shih-Lei Lai, Didier Y. R. Stainier and Arica Beisaw ()
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Florian Constanty: Heidelberg University
Bailin Wu: Heidelberg University
Ke-Hsuan Wei: Academia Sinica
I-Ting Lin: Academia Sinica
Julia Dallmann: Max Planck Institute for Heart and Lung Research
Stefan Guenther: Max Planck Institute for Heart and Lung Research
Till Lautenschlaeger: Max Planck Institute for Heart and Lung Research
Rashmi Priya: Max Planck Institute for Heart and Lung Research
Shih-Lei Lai: Academia Sinica
Didier Y. R. Stainier: Max Planck Institute for Heart and Lung Research
Arica Beisaw: Heidelberg University

Nature Communications, 2025, vol. 16, issue 1, 1-25

Abstract: Abstract Despite numerous advances in our understanding of zebrafish cardiac regeneration, an aspect that remains less studied is how regenerating cardiomyocytes invade and replace the collagen-containing injured tissue. Here, we provide an in-depth analysis of the process of cardiomyocyte invasion. We observe close interactions between protruding border-zone cardiomyocytes and macrophages, and show that macrophages are essential for extracellular matrix remodeling at the wound border zone and cardiomyocyte protrusion into the injured area. Single-cell RNA-sequencing reveals the expression of mmp14b, encoding a membrane-anchored matrix metalloproteinase, in several cell types at the border zone. Genetic mmp14b mutation leads to decreased macrophage recruitment, collagen degradation, and subsequent cardiomyocyte protrusion into injured tissue. Furthermore, cardiomyocyte-specific overexpression of mmp14b is sufficient to enhance cardiomyocyte invasion into the injured tissue and along the apical surface of the wound. Altogether, our data provide important insights into the mechanisms underlying cardiomyocyte invasion of the collagen-containing injured tissue during cardiac regeneration.

Date: 2025
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DOI: 10.1038/s41467-025-59169-4

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