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Fibrin defines tissue stiffness and biomechanical signalling in regenerating zebrafish hearts as revealed by high-resolution stiffness mapping

ABSTRACT: The infarction of the human heart leads to irreversible scar formation, which permanently impairs its mechanical properties and physiological functions. Interestingly, the zebrafish heart is capable of resolving scar tissue and regenerating injured myocardium, offering a unique opportunity to study the interplay between scar tissue and cardiac mechanical properties during regeneration. In this study, we developed a novel method combining atomic force microscope-based nanoindentation with confocal microscopy to generate an elasticity map of the zebrafish heart. This high-resolution mapping revealed distinct regions of stiffness within the injury site, despite the overall global mechanical properties remaining unaffected. Specifically, we identified a stiff area that is cell-poor and fibrin-rich, contrasting with the center of injury, which is as soft as the surrounding myocardium. Extensive whole transcriptome analyses uncovered several components of the coagulation and fibrinolysis cascade in the regenerating heart. Pharmacological inhibition of Serpine1, a regulator of fibrinolysis, demonstrated that reduced fibrin-mediated stiffness impacts the activation of biomechanical Hippo pathway signaling in adjacent endocardial cells. Our approach characterizes the mechanical properties of different regions in the zebrafish ventricle, highlighting fibrin as the stiffest element influencing biomechanical signaling. This suggests it may play a structural role in the regeneration process. The methodology presented here offers a detailed view of the biomechanical environment and mechanotransductive signaling in regenerating cardiac tissue, which is crucial for understanding regenerative mechanisms.

ORGANISM(S): Danio rerio

PROVIDER: GSE297624 | GEO | 2025/12/10

REPOSITORIES: GEO

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Project description:Ischemic cardiopathy is the leading cause of death in the world, for which efficient regenerative therapy is not currently available. In mammals, after a myocardial infarction episode, the damaged myocardium is replaced by scar tissue featuring collagen deposition and tissue remodelling with negligible cardiomyocyte proliferation. Zebrafish, in contrast, display an extensive regenerative capacity as they are able to restore completely lost cardiac tissue after partial ventricular amputation. Due to the lack of genetic lineage tracing evidence, it is not yet clear if new cardiomyocytes arise from existing contractile cells or from an uncharacterised set of progenitors cells. Nonetheless, several genes and molecules have been shown to participate in this process, some of them being cardiomyocyte mitogens in vitro. Though questions as what are the early signals that drive the regenerative response and what is the relative role of each cardiac cell in this process still need to be answered, the zebrafish is emerging as a very valuable tool to understand heart regeneration and devise strategies that may be of potential value to treat human cardiac disease. Here, we performed a genome-wide transcriptome profile analysis focusing on the early time points of zebrafish heart regeneration and compared our results with those of previously published data. Our analyses confirmed the differential expression of several transcripts, and identified additional genes the expression of which is differentially regulated during zebrafish heart regeneration. We validated the microarray data by conventional and/or quantitative RT-PCR. For a subset of these genes, their expression pattern was analyzed by in situ hybridization and shown to be upregulated in the regenerating area of the heart. The specific role of these new transcripts during zebrafish heart regeneration was further investigated ex vivo using primary cultures of zebrafish cardiomyocytes and/or epicardial cells. Our results offer new insights into the biology of heart regeneration in the zebrafish and, together with future experiments in mammals, may be of potential interest for clinical applications. In order to study zebrafish heart regeneration, a time course experiment was realized where amputated heart regenerating were compared to control heart. Samples in triplicate were extracted at 1, 3, 5 and 7 days post-amputation.

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Fibrin defines tissue stiffness and biomechanical signalling in regenerating zebrafish hearts as revealed by high-resolution stiffness mapping

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