The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration (dst169)
The innate immune system is triggered rapidly after injury and its spatiotemporal dynamics are critical for successful regeneration.  MyD88 is a key component of the innate immune response; however, its role during regeneration remains unclear.  Here we show that MyD88 controls not only the inflammatory but also the fibrotic response during zebrafish cardiac regeneration.  Our data reveal a significant reduction in pro-inflammatory neutrophil and macrophage populations, as well as the expansion of a collagen-rich endocardial population in cryoinjured myd88-/- ventricles.  Consistent with these findings, we observed increased myofibroblasts, fibrin abundance, and scarring in myd88-/- ventricles.  Transcriptomic analyses of endocardial cells and immunostaining experiments reveal compromised PI3K/AKT pathway activation in the myd88-/- endocardium.  Moreover, loss of MyD88 impairs cardiomyocyte proliferation and protrusive activity towards the injured area.  Notably, endothelial-specific overexpression of myd88 reverses the neutrophil, fibrotic, and scarring phenotypes in cryoinjured myd88-/- ventricles.  Mechanistically, we identify the endocardial-derived chemokine gene cxcl18b as a transcriptional target of the MyD88-signaling axis and using loss- and gain-of-function tools show that it controls neutrophil recruitment.  Altogether, these findings shed light on the pivotal role of MyD88 in modulating inflammation and fibrosis, thereby emphasizing the strong impact of the innate immune response during tissue regeneration. Overall design: Live zebrafish ventricular cells were isolated at 24 hour post cryoinjury (hpci) from myd88+/+ and myd88-/- ventricles by Fluorescence-activated cell sorting (FACS) and analyzed using scRNAseq.