Uncovering Molecular Cues Regulating Response to Injury in the Adult Zebrafish Heart

About This Grant

Abstract: The adult zebrafish is capable of rapid regenerative processes in response to cardiac damage that result in a fully functional and scarless heart. This robust regenerative response is controlled by pre-existing populations of cardiomyocytes that de-differentiate prior to proliferation in response to injury; however, the full extent of intercellular signaling that facilitates the injury-response of these cardiomyocytes remains unknown. A subpopulation of cardiomyocytes in the zebrafish heart are derived from the cardiac neural crest (CNC), a highly migratory stem cell population in the early vertebrate embryo. These neural crest-derived cardiomyocytes (NCCMs) may contribute extensively to regeneration in the adult heart by reactivating developmental gene networks, including those controlling morphogenesis in the early embryo. In particular, the cxcr4b/cxcl12a chemokine signaling pathway is known to be essential for CNC migration in the developing embryo and regulates aspects of migration in the regenerating heart. To assess the roles of cxcr4b/cxcl12a in relation to the CNC during cardiac regeneration in the adult, I will conduct mRNA expression and localization analyses via hybridization chain reaction (HCR), in vitro migration assays of primary cardiomyocyte cultures, and create transgenic fish lines for the conditional overexpression and knockout of cxcl12a and cxcr4b, respectively, during cardiac regeneration in the adult. I will also analyze existing cardiac ATAC-seq data to identify and validate putative damage-responsive enhancer regions that drive chemokine gene expression. Identifying how migratory mechanisms guide cardiomyocytes will assist in discovering therapeutic approaches aimed at stimulating human hearts with a regenerative capacity.