What is the clinical evidence from this study?

Study design: Other. Population: Myocardial infarction. Intervention: Genetic lineage tracing and single cell RNA-sequencing. Primary outcome: Monocyte differentiation trajectories.

December 25, 2023Open Access

Genetic Mapping of Monocyte Fate Decisions Following Myocardial Infarction

Key Result

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.

Structured PICO

Population

Mus musculus (mice) on C57BL/6 background, 6-12 weeks of age, equal numbers of male and female, subjected to closed-chest ischemia reperfusion injury to model reperfused myocardial infarction. Strains include Ccr2CreERT2Rosa26LSL-tdTomato, Cx3cr1CreERT2Rosa26LSL-tdTomato, and Ccr2CreERT2Ifnar1Flox.

Exposure

Selective deletion of Ifnar1 in recruited monocytes and their progeny using Ccr2CreERT2Ifnar1Flox mice treated with tamoxifen.

Comparator

Control mice subjected to the same myocardial infarction model.

Outcome

Post-MI remodeling assessed by echocardiography (end systolic and diastolic left ventricular volumes, akinetic area) and histology (cardiomyocyte hypertrophy, infarct size) at day 28 post-injury.surrogate

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

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.

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