Fate-mapping infiltrating monocytes following experimental myocardial infarction reveals differentiation trajectories...

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 striking 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 Ccr2crERT2Rosa26LSL-tdTomato mice in combination with single cell RNA-seq to map the differentiation trajectories of monocytes that infiltrate the heart after reperfused myocardial infarction. Monocytes were recruited to the heart early after injury and gave rise to transcriptionally distinct and spatially restricted macrophage and dendritic cell-like subsets that were specified prior to extravasation and chronically persisted within the myocardium. Pseudotime analysis predicted 2 differentiation trajectories of monocyte-derived macrophages that are partitioned into the border and infarct zones, respectively. Among these trajectories, we demonstrated that macrophages expressing a type I interferon-responsive signature were an intermediate population that gave rise to MHC-IIhi macrophages, were localized within the border zone, induce regulatory T cells, and promote myocardial protection. Collectively, these data uncover complexities of monocyte differentiation in the infarcted heart and suggest that modulating monocyte fate decisions may have clinical implications.