Abstract 106: Cardiac Fibroblast as a Critical Constituent of the Cellular Niche Driving Cardiac Maturation

Rationale: Cardiac maturation lays the foundation of postnatal heart development and disease, yet little is known about the contributions of the microenvironment to cardiomyocyte maturation. Objective: To identify non-cardiomyocyte cell types and important signaling pathways central to cardiomyocyte maturation. Methods and Results: Through building cell-cell interactomes and signaling regulatory networks from single-cell RNA-sequencing data of mouse hearts at various postnatal stages, we identified switching of fibroblast subclusters state as a key driving force behind cardiac maturation. Molecular and functional maturation of immature (neonatal) mouse cardiomyocytes or human embryonic stem cell-derived cardiomyocytes were considerably enhanced when co-cultured with their corresponding adult cardiac fibroblasts in vitro . Further, single-cell analysis of the cardiac maturation trajectory revealed highly conserved signaling pathways and ligands in fibroblast-induced cardiomyocyte maturation in vivo and in vitro . Targeting these signaling pathways using inhibitors significantly delayed cardiac maturation in postnatal hearts, and markedly induced cardiomyocyte proliferation in infarcted hearts. Conclusions: Our study unveiled cardiac fibroblasts as a major constituent in the microenvironment driving cardiac maturation. Targeting signaling pathways and ligand-receptor interactions involved in their crosstalk with cardiomyocytes may yield useful strategies to modulate cardiomyocyte maturation state in cardiac diseases and for regeneration purposes. Keywords: Cardiac Maturation, Fibroblast, Single-Cell RNA-Sequencing