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Border-zone cardiomyocytes and macrophages contribute to remodeling of the extracellular matrix to promote cardiomyocyte invasion during zebrafish cardiac regeneration

ABSTRACT: Despite numerous advances in our understanding of zebrafish cardiac regeneration, an aspect that remains less studied is how newly proliferated cardiomyocytes invade, and eventually replace, the collagen-containing fibrotic tissue following injury. Here, we provide an in-depth analysis of the process of cardiomyocyte invasion and migration using live-imaging and histological approaches. We observed a close interaction between protruding cardiomyocytes and macrophages at the wound border zone, and irf8 mutant zebrafish, which largely lack macrophages, exhibited defects in extracellular matrix (ECM) remodeling and cardiomyocyte protrusion into the injured area. Using a resident macrophage ablation model, we show that defects in ECM remodeling at the border zone and subsequent cardiomyocyte protrusion can be partly attributed to a population of resident macrophages. Single-cell RNA-sequencing analysis of cells at the wound border revealed a population of cardiomyocytes and macrophages with fibroblast-like gene expression signatures, including the expression of genes encoding ECM structural proteins and ECM-remodeling proteins. The expression of mmp14b, which encodes a membrane-anchored matrix metalloproteinase, was restricted to cells in the border zone and genetic deletion of mmp14b led to a decrease in 1) collagen degradation at the border zone, 2) macrophage recruitment to the border zone, and 3) subsequent cardiomyocyte invasion. Furthermore, cardiomyocyte-specific overexpression of mmp14b was sufficient to enhance cardiomyocyte invasion both into the injured area and along the apical surface of the wound. Altogether, our data shed important insights into the process of cardiomyocyte invasion of the collagen-containing injured tissue during cardiac regeneration. They further suggest that cardiomyocytes and resident macrophages contribute to ECM remodeling at the border zone to promote cardiomyocyte replenishment of the fibrotic injured tissue.

ORGANISM(S): Danio rerio

PROVIDER: GSE251856 | GEO | 2025/03/11

REPOSITORIES: GEO

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Project description:Myocardial infarction results in a massive loss of cardiomyocytes which will not be regenerated. Recent studies using models of regeneration show that cardiomyocytes at the border of the injury are most prone to proliferate. Which processes occur in this region and make these cells act as progenitors, remains to be elucidated. In addition, we lack molecular markers for the identification of these cells in the human heart. To create a transcriptional profile of the murine border zone, identifying local processes and enabling the discovery of marker genes which will allow the identification of human cardiomyocytes with potential proliferative capacity. Myocardial infarction (MI) was induced in mice and 3, 7 or 14 days later ventricular tissue was isolated ranging from the injured area into the remote myocardium. Tomo-sequencing was performed on these cardiac tissue samples, which comprises of tissue sectioning together with RNA-sequencing on individual sections. This resulted in spatially resolved transcriptome maps containing a dynamic, transcriptionally distinct border zone with reduced expression of genes involved in mitochondrial oxidative phosphorylation, fatty acid metabolism and sarcomere function and increased expression of myofibroblast and proliferation genes. Genes shared between the murine and zebrafish border zone, such as ANKRD1, UCHL1 and DES, were validated as molecular markers in injured human hearts. Unexpectedly, pronounced expression of these marker genes was found in surviving cardiomyocytes located at the sub-endocardium. The border zone is an evolutionary conserved, transcriptionally distinct and dynamic region. With the use of newly identified markers, we discovered the existence of sub-endocardial cardiomyocytes in ischemic human hearts that share transcriptional characteristics with potential progenitor cells. This might have far reaching implications for the development of strategies to stimulate the regenerative capacity of patients suffering from ischemic injury.

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Border-zone cardiomyocytes and macrophages contribute to remodeling of the extracellular matrix to promote cardiomyocyte invasion during zebrafish cardiac regeneration

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