1 International Res. Center for Med. Sci., Kumamoto Univ. 2 Molecular Cellular Developmental Biology, Univ. of California, Los Angeles.3 Dept. of Cell Physiology, The Jikei Univ. Sch. of Med.interaction with blood vesselsEndocardium-derived macrophages prevent cardiac fibrosis through IntroductionWe have previously demonstrated that endocardial cells transiently acquire hematopoietic potential during development and give rise to macrophages (MΦs) critical for endocardial cushion remodeling. Notably, endocardial-derived MΦs (Endo-MΦs) exhibit higher phagocytic activity than those from other origins (Shigeta et al, Dev Cell. 2019; Liu et al, Nat Commun. 2023). While Endo-MΦs persist in the adult heart, their functional role remains unclear.MethodsTo investigate the lifelong role of Endo-MΦs, we utilized lineage tracing (Nfatc1-Cre or Nkx2-5-Cre; R26-tdTomato), ablation models (Nkx2-5-Cre; Csf1r-fl/fl), and transcriptomic analysis. We assessed their localization, contribution to cardiac fibrosis, and age-related gene expression using the Tabula Muris Senis dataset.Results & ConclusionsEndo-MΦs persist into adulthood as tissue-resident macrophages, predominantly in the valve endocardium and perivascular regions. Their ablation resulted in increased cardiac fibrosis, indicating a protective role. Transcriptomic profiling revealed that Endo-MΦs express genes associated with antifibrotic signaling and vascular interaction, suggesting they maintain cardiac homeostasis partly by modulating the perivascular niche. These findings uncover a previously unrecognized long-term function of endocardially derived macrophages in suppressing cardiac fibrosis and promoting tissue integrity with aging.○Norika Liu1,2 Atsushi Nakano2, 336P 006
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