Genetic Mapping of Monocyte Fate Decisions Following Myocardial Infarction

Area of Science:

• Cardiovascular Biology
• Immunology
• Regenerative Medicine

Background:

• Inflammation is central to myocardial infarction (MI) and heart failure pathogenesis.
• Monocytes and their diverse progeny critically influence cardiac inflammation and repair post-MI.
• Mechanisms governing monocyte fate decisions in the injured heart require further elucidation.

Purpose of the Study:

• To map monocyte differentiation trajectories within the infarcted heart using genetic lineage tracing and single-cell RNA sequencing.
• To identify distinct monocyte-derived macrophage and dendritic cell subsets and their spatial distribution.
• To explore the functional roles of specific macrophage populations in myocardial protection.

Main Methods:

• Utilized Ccr2-reporter mice for genetic lineage tracing of infiltrating monocytes.
• Employed single-cell RNA sequencing to analyze transcriptional profiles of cardiac immune cells post-MI.
• Applied pseudotime analysis to infer differentiation pathways of monocyte-derived macrophages.

Main Results:

• Monocytes infiltrate the heart early after reperfused MI, differentiating into distinct subsets before or upon extravasation.
• Two spatially segregated monocyte-derived macrophage populations were identified in the infarct and border zones.
• An intermediate macrophage population expressing a type I IFN-responsive signature was found to give rise to protective MHC-IIhi macrophages in the border zone.

Conclusions:

• Monocyte differentiation in the infarcted heart is complex, yielding transcriptionally distinct and persistent immune cell subsets.
• Specific macrophage subsets, particularly MHC-IIhi macrophages in the border zone, are implicated in myocardial protection.
• Modulating monocyte fate presents a potential therapeutic strategy for managing heart failure post-MI.