Mapping macrophage polarization over the myocardial infarction time continuum

Area of Science:

• Cardiovascular Biology
• Immunology
• Cellular and Molecular Medicine

Background:

• Cardiac macrophages are crucial for regulating inflammation and scar formation following myocardial infarction (MI).
• Understanding temporal changes in macrophage polarization is vital for developing targeted therapies after heart attack.

Purpose of the Study:

• To investigate the dynamic transcriptomic changes and polarization states of cardiac macrophages during the initial week after myocardial infarction (MI).
• To identify key molecular events and cellular functions associated with macrophage reprogramming in the infarcted heart.

Main Methods:

• Induction of MI in C57BL/6J male mice via coronary artery ligation.
• Isolation of cardiac macrophages from the infarct region at days 1, 3, and 7 post-MI for whole transcriptome analysis using RNA-sequencing.
• Flow cytometry and in situ hybridization were used to validate macrophage phenotypes and gene expression in vivo.

Main Results:

• Day 1 macrophages exhibited a pro-inflammatory and extracellular matrix (ECM)-degrading signature, with infiltrating monocytes (F4/80lowLy6Chigh) dominating.
• Day 3 macrophages showed increased proliferation, phagocytosis, and metabolic reprogramming, indicated by enhanced mitochondrial function and oxidative phosphorylation gene expression.
• Day 7 macrophages displayed a pro-reparative signature, expressing genes for ECM remodeling, scar formation (Collagen I, Periostin), and acting as a direct source of ECM components.

Conclusions:

• Macrophages undergo significant and distinct transcriptomic shifts throughout the first week following MI, crucial for cardiac healing.
• Metabolic reprogramming plays a critical role in macrophage polarization and functional adaptation post-MI.
• Macrophages are not only mediators but also direct contributors to ECM remodeling during cardiac repair after MI.