(A) In the embryonic heart, most fibroblasts are derived from epicardium (pink). The fibroblast lineage described by Moore-Morris et al. is generated from the atrioventricular canal endocardium (green) and migrates down the IVS. (B) In the adult heart, the dominant fraction of fibroblasts (∼90%) in the RV and LV are of epicardial origin, while 64% of fibroblasts in the IVS derive from the endocardium. (C) In response to pressure overload, the heart becomes hypertrophic and undergoes fibrosis. In response to pressure overload, both epicardium-derived and endocardium-derived fibroblast lineages proliferate and accumulate in interstitial and perivascular regions along with collagen I (black). The LV undergoes more fibrosis than the RV. Endocardium-derived fibroblasts participate in perivascular fibrosis in the IVS but not in the LV or RV. These two resident lineages account for approximately 95% of fibroblasts in the healthy and pressure-overloaded ventricles.