Abstract

Summary Understanding cellular origins of cardiac adipocytes (CAs) can offer important implications for the treatment of fat-associated cardiovascular diseases. Here, we perform lineage tracing studies by using various genetic models and find that cardiac mesenchymal cells (MCs) contribute to CAs in postnatal development and adult homeostasis. Although PDGFRa + and PDGFRb + MCs both give rise to intramyocardial adipocytes, PDGFRb + MCs are demonstrated to be the major source of intramyocardial adipocytes. Moreover, we find that PDGFRb + cells are heterogenous, as PDGFRb is expressed not only in pericytes and smooth muscle cells (SMCs) but also in some subendocardial, pericapillary, or adventitial PDGFRa + fibroblasts. Dual-recombinase-mediated intersectional genetic lineage tracing reveals that PDGFRa + PDGFRb + double-positive periendothelial fibroblasts contribute to intramyocardial adipocytes. In contrast, SMCs and NG2 + pericytes do not contribute to CAs. These in vivo findings demonstrate that PDGFRb + MCs, but not NG2 + coronary vascular mural cells, are the major source of intramyocardial adipocytes.