Dual genetic lineage tracing identifies a unique fibroblast subpopulation mediating cardiac fibrosis

After 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 the degree of their activation, proliferation and function during cardiac fibrosis. By dual recombinases-mediated genetic lineage tracing, we found that endocardium-derived fibroblasts (EndoFb) preferentially proliferate and expand in response to pressure overload injury. 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 improves heart function after injury. Mechanistically, Wnt signaling promotes activation and expansion of EndoFb after cardiac injury. Here, we have identified EndoFb as a key fibroblast subpopulation accounting for severe cardiac fibrosis, and their targeting could be a potential therapeutic treatment for cardiac fibrosis.