Toll-like receptor 3orchestrates a conserved mechanism of heart regeneration

Abstract

AbstractThe human’s heart responds to tissue damage with persistent fibrotic scarring. Unlike humans, zebrafish can repair cardiac injury and re-grow heart tissue throughout life. Recently,Toll-like receptor 3(Tlr3) was identified as an important mediator of cardiac regeneration in neonatal mice. However, no functional analysis oftlr3knock-out mutant zebrafish in respect to cardiac regeneration has yet been performed.We hypothesize that TLR3 signalling plays a central, conserved role in driving cardiac regeneration upon injury. Therefore, we focused ontlr3mediated cardiac regeneration in zebrafish, ultimately discovering an evolutionary conserved mechanism of heart repair. Using histological, behavioural, and RNA-Sequencing analysis, we uncovered a conserved mechanism oftlr3mediated cardiac repair after myocardial injury.Upon myocardial cryoinjury subjection, survival is decreased intlr3-/-fish as compared to wildtype controls.Tlr3-/-zebrafish fail to recruit immune cells to the injured ventricle, resulting in impaired DNA repair and transcriptional reprogramming of cardiomyocytes.Mechanistically, we uncover an evolutionary conserved mechanism oftlr3activation in fibroblasts promoting monocyte migration towards an injured ventricular area. Our data revealtlr3as a novel therapeutic target to promote cardiac regeneration.Every experiment including human participants has been approved by the ethics committee of the Medical University of Innsbruck (Ref. Nr.: 1262/2023). All experiments including the use of laboratory animals have been approved by the federal ministry of education, science, and research of Austria (Ref. Nr.: 2020-0.345.504).