Genetic lineage tracing in mice revealed that monocytes recruited after myocardial infarction differentiate into distinct macrophage subsets, including a protective type I IFN-responsive population.
Genetic lineage tracing and single-cell RNA sequencing reveal that monocytes differentiate into spatially restricted macrophage subsets after MI, and type I interferon signaling in these macrophages protects against adverse left ventricular remodeling.
Abstract Inflammation contributes to the pathogenesis of myocardial infarction and heart failure and represents a viable therapeutic target. Monocytes and their progeny are highly abundant and display incredible functional diversity, serving as key determinants of myocardial inflammation and tissue repair. Much remains to be learned regarding mechanisms and signaling events that instruct monocyte fate decisions. We devised a genetic lineage tracing strategy using Ccr2 crERT2 Rosa26 LSL-tdTomato mice in combination with single cell RNA-sequencing to map the differentiation trajectories of monocytes that infiltrate the heart after reperfused myocardial infarction. Monocytes are recruited to the heart early after injury and give rise to transcriptionally distinct and spatially restricted macrophage and dendritic cell-like subsets that are specified prior to extravasation and chronically persist within the myocardium. Pseudotime analysis predicted two differentiation trajectories of monocyte-derived macrophages that are partitioned into the border and infarct zones, respectively. Among these trajectories, we show that macrophages expressing a type I IFN responsive signature are an intermediate population that gives rise to MHC-II hi macrophages, are localized within the border zone, and promote myocardial protection. Collectively, these data uncover new complexities of monocyte differentiation in the infarcted heart and suggest that modulating monocyte fate decisions may have clinical implications.
Koenig et al. (2023) studied Myocardial infarction. Genetic lineage tracing and single cell RNA-sequencing was evaluated on Monocyte differentiation trajectories. Genetic lineage tracing in mice revealed that monocytes recruited after myocardial infarction differentiate into distinct macrophage subsets, including a protective type I IFN-responsive population.