Endocardium Contributes to Cardiac Fat

Abstract

Rationale: Unraveling the developmental origin of cardiac fat could offer important implications for the treatment of cardiovascular disease. The recent identification of the mesothelial source of epicardial fat tissues reveals a heterogeneous origin of adipocytes in the adult heart. However, the developmental origin of adipocytes inside the heart, namely intramyocardial adipocytes, remains largely unknown. Objective: To trace the developmental origin of intramyocardial adipocytes. Methods and Results: In this study, we identified that the majority of intramyocardial adipocytes were restricted to myocardial regions in close proximity to the endocardium. Using a genetic lineage tracing model of endocardial cells, we found that Nfatc1 + endocardial cells contributed to a substantial number of intramyocardial adipocytes. Despite the capability of the endocardium to generate coronary vascular endothelial cells surrounding the intramyocardial adipocytes, results from our lineage tracing analyses showed that intramyocardial adipocytes were not derived from coronary vessels. Nevertheless, the endocardium of the postnatal heart did not contribute to intramyocardial adipocytes during homeostasis or after myocardial infarction. Conclusions: Our in vivo fate-mapping studies demonstrated that the developing endocardium, but not the vascular endothelial cells, gives rise to intramyocardial adipocytes in the adult heart.

Atrial natriuretic peptide regulates adipose tissue accumulation in adult atria

“…A similar phenomenon of mesenchymal transformation and adipogenic differentiation of epicardial progenitors has been reported in the atrioventricular canal during embryonic development (11,40). Of note, the endocardium has been shown to contribute to cardiac adipocytes during development, but adult endocardial-to-fat transition has not yet been reported (41).…”

Preexisting endothelial cells mediate cardiac neovascularization after injury

“…Col1a2-CreER transgene (14), Tcf21-MerCreMer (24), PostnMerCreMer (6), Cdh5-CreER (27), Apln-CreER (28), Fabp4-CreER (29), R26R-tdTomato (16), R26R-rox-tdTomato (22), and R26R-GFP (46) mouse lines were previously described. Sox9-CreER was generated by homologous recombination using CRISPR/Cas9 methods (21).…”

“…Dre-rox recombination removes rox-flanked transcriptional stop cassette, resulting in permanent expression of tdTomato and irreversible labeling of all descendants (20, 21) ( Figure 3B). We crossed Pdgfra-DreER to the R26R-rox-tdTomato reporter line (22) and treated adult Pdgfra-DreER R26R-rox-tdTomato mice with tamoxifen to induce PDGFRA + cell labeling. Flow cytometric analysis of isolated fibroblasts or endothelial cells showed that approximately 50% of PDGFRA + fibroblasts without a distinct population of PECAM + endothelial cells were tdTomato + ( Figure 3, C and D), suggesting that Pdgfra-DreER efficiently and specifically labeled fibroblasts, but not endothelial cells.…”

Genetic lineage tracing identifies endocardial origin of liver vasculature

“…Because we found that the caudal part of the endocardium is located in proximity to the foregut endoderm and liver bud at times of hepatic vessel formation, we investigated whether the endocardium forms liver vasculature in addition to coronary arteries. To lineage trace the developing endocardium, we first crossed Nfatc1-dre mice with the rox reporter line Rosa26-rox-STOP-rox-RFP (Rosa26-RSR-RFP) to generate Nfatc1-dre; Rosa26-RSR-RFP embryos 21 . Dre, like Cre, is a site-specific recombinase and targets rox sites for recombination; it has previously been used for lineage tracing [22][23][24] .…”