Early exercise disrupts a pro-repair extracellular matrix program during zebrafish fin regeneration

Abstract

Mechanical stimulation effects on cell behaviors that restore organ form and function during tissue repair are unresolved. We applied swim flume-mediated exercise during zebrafish caudal fin regeneration to explore mechanical loading impacts on a robust model of organ regeneration. Exercise initiated during but not after blastema establishment compromised fin regeneration, including outgrowth and skeletal pattern. Long-term tracking of fluorescently labeled fibroblasts showed exercise loading disrupted blastemal mesenchyme formation. Transcriptomic profiling and section staining indicated loading reduced an extracellular matrix (ECM) gene expression program, including for hyaluronic acid (HA) synthesis. As with exercise loading, HA synthesis inhibition or blastemal HA depletion impaired blastema formation. We considered if injury-upregulated HA establishes a pro-regenerative environment facilitating mechanotransduction. HA density across the blastema correlated with nuclear localization of the mechanotransducer Yes-associated protein (Yap). Exercise loading or HA depletion decreased nuclear Yap, and culturing primary fin fibroblasts on HA-coated surfaces induced Yap nuclear localization. We conclude early exercise during fin regeneration disrupts expression of an HA-rich ECM supporting Yap-promoted blastema expansion. These findings reveal that fin regeneration is acutely sensitive to the timing and intensity of mechanical loading, underscoring how biomechanical forces integrate with regenerative programs to guide robust tissue repair.