Dual genetic tracing reveals a unique fibroblast subpopulation modulating cardiac fibrosis

After severe heart injury, fibroblasts are activated and proliferate excessively to form scar, leading to decreased cardiac function and eventually heart failure. It is unknown, however, whether cardiac fibroblasts are heterogeneous in respect of their degree of activation, proliferation, and function during cardiac fibrosis. Here, by dual recombinases-mediated genetic lineage tracing, we found that endocardium-derived fibroblasts (EndoFb) preferentially proliferate and expand in response to pressure overload. Fibroblast-specific proliferation tracing revealed highly regional expansion of activated fibroblasts after injury, the pattern of which mirrors that of EndoFb distribution in the heart. Specific ablation of EndoFb alleviates cardiac fibrosis and reduces the decline of heart function after pressure overload injury. Mechanistically, Wnt signaling promotes activation and expansion of EndoFb during cardiac remodeling. Our study identified EndoFb as a key fibroblast subpopulation accounting for severe cardiac fibrosis after pressure overload injury, and as a potential therapeutic target against cardiac fibrosis.