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

Myocardial infarction in humans causes an irreversible scar, which permanently impairs cardiac mechanical properties and physiological functions. The zebrafish heart resolves scar tissue and regenerates injured myocardium. To study mechanical properties during regeneration, we developed a method combining atomic force microscope-based nanoindentation with confocal microscopy and generated a high-resolution elasticity map of the zebrafish heart. This revealed distinct regions of stiffness within the injury site, including a stiff area that is cell-poor and fibrin-rich, contrasting with the softer injury center and surrounding myocardium. Whole-transcriptome analyses uncovered several components of the coagulation and fibrinolysis cascades in the regenerating heart. Pharmacological inhibition of the fibrinolysis regulator Serpine1 demonstrated that reduced fibrin-mediated stiffness impacts the biomechanical Hippo pathway in adjacent endocardial cells. Our approach characterizes the mechanical properties of different regions in the regenerating heart and shows that the biomechanical environment and mechanotransductive signaling are crucial components for understanding regenerative mechanisms.