Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction

Macrophages promote both injury and repair after myocardial infarction, but discriminating functions within mixed populations remains challenging. Here we used fate mapping, parabiosis and single-cell transcriptomics to demonstrate that at steady state, TIMD4⁺LYVE1⁺MHC-II^loCCR2⁻ resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes partially replaced resident TIMD4^–LYVE1^–MHC-II^hiCCR2⁻ macrophages and fully replaced TIMD4⁻LYVE1⁻MHC-II^hiCCR2⁺ macrophages, revealing a hierarchy of monocyte contribution to functionally distinct macrophage subsets. Ischemic injury reduced TIMD4⁺ and TIMD4^– resident macrophage abundance, whereas CCR2⁺ monocyte-derived macrophages adopted multiple cell fates within infarcted tissue, including those nearly indistinguishable from resident macrophages. Recruited macrophages did not express TIMD4, highlighting the ability of TIMD4 to track a subset of resident macrophages in the absence of fate mapping. Despite this similarity, inducible depletion of resident macrophages using a Cx3cr1-based system led to impaired cardiac function and promoted adverse remodeling primarily within the peri-infarct zone, revealing a nonredundant, cardioprotective role of resident cardiac macrophages.