The origin of fat cells or adipocytes is a fundamental biological question with important ramifications for human health and disease1. Epicardial fat is associated with increased risk of cardiovascular diseases such as coronary atherosclerosis2. However, the origin of these epicardial fat cells remains largely unknown. Epicardial progenitors play a pivotal role in the developing heart, by secreting paracrine signals and by differentiating into fibroblasts, smooth muscle cells, and potentially endothelial cells and cardiomyocytes3,4,5,6. Some of these developmental programs are reactivated during postnatal heart injury7,8, and reactivated adult epicardial progenitors provide pro-angiogenic protection and undergo limited epithelial-to-mesenchymal transition in cardiac injury7,9. Since epicardial fat is physically adjacent to epicardial cells, we hypothesized that some of these cells originate from the epicardium during development and in postnatal heart injury.

To further confirm this finding, we employed an adenovirus that expresses Cre under the epicardium-specific promoter Msln to selectively lineage-trace the epicardium7. Ad:Msln-Cre transduction of cultured epicardial cells activated expression of GFP from a Cre-dependent Rosa26mTmG/+ reporter (Supplementary information, Figure S1B). As Msln is specifically expressed in epicardium of the developing heart (Supplementary information, Figure S1C), we performed ultrasound-guided embryonic heart injection of Msln-Cre virus at E12.5. Examination of E15.5 hearts confirmed selective labeling of the epicardium (Supplementary information, Figure S1D). We next collected P8w hearts and found that a subset of Msln-Cre-labeled EPDCs co-expressed PLIN, demonstrating contribution of epicardial progenitors to fat cells during normal heart development (Figure 1D). Altogether, the above data showed that embryonic epicardial progenitors contribute to epicardial fat. We refer to this process as epicardium-to-fat transition (EFT).

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