Keratin5-cytoskeleton-BMP4 network regulates cell phenotype conversions during cardiac regeneration.

The reconstruction of a blood supply system and myocardial recovery from inflamamtory reactions in the infract zone remains a challenge in cardiac regeneration after myocardial infarction. Here, we observed that the local myocardial cells and the clotted blood cells undergo cellular remodeling via cytoplasmic exocytosis and nuclear reorganization in zebrafish hearts after resection of the ventricular apex. The subsequent tissue regeneration processes were visualized by detection of the spatiotemporal expression of three tissue specific genes (α-SMA which marks for vasculature/fibrogenesis, Flk1for angiogenesis/hematopoiesis, and Pax3a for remusculogensis), and two histone modification markers (H3K9Ac and H3K9Me3 for chromatin remodeling). By analyzing the composition of the blastema tissue fractions we found that Krt5 peptide could promote F-actin assembly, BMP4-pSmad2/5/8 signaling activity, and H3K9Me3-mediated chromatin accessibility at the blastema representative genes in the cultured zebrafish embryonic fibroblasts. Further in vivo tests demonstrated that Krt5 interacted with beta actin, and promoted Gata3 expression and Flk1-GFP marked blastema angiogenesis. These results proposed a new Krt5-cytoskeleton-BMP4 mechanotransduction mechanism in the epithelial-dependent and cell phenotype conversion-based tissue regeneration.