In silico analysis of putative interactions identifies fibroblasts as hubs for cell-cell communication during early regeneration of the zebrafish heart.

Background The zebrafish heart regenerates upon injury. During injury response, fibroblasts and endothelial cells accumulate at the site of damage, and cardiomyocyte cell cycle reentry allows cardiac muscle regrowth. It is relevant to understand how the different cell types communicate with each other to coordinate regeneration.Results We present an in silico meta-analysis of ligand-receptor (LR) interactions among periostin b+ fibroblasts, kdlr+ endothelial cells, sox10-derived and rest of ventricular cardiomyocytes, at 7 days post-injury. Using bulk RNA-seq data sets from fluorophore-activated cell-sorted populations, we selected for differentially expressed genes encoding LR pairs. Human-centric interaction data from the OmniPath database were adapted to zebrafish data through ortholog mapping to reconstruct a comprehensive interactome. We observed that fibroblasts and, to a lesser extent, endothelial cells emerged as signaling hubs, while cardiomyocytes primarily acted as signal recipients. Network analysis, combining PageRank, expression change, and literature-based novelty, revealed both known and novel candidate genes in regeneration, and allowed pathway enrichment analysis. An interactive web tool enables exploration of the ranked interaction data set, providing a systematic resource to guide future functional studies.Conclusions This study provides a systematic and unbiased map of regenerative signaling in the zebrafish heart, establishing a resource to guide functional investigations.