Regenerative cross talk between cardiac cells and macrophages

Area of Science:

• Cardiovascular Biology
• Regenerative Medicine
• Immunology

Background:

• Murine heart regeneration is robust in the first postnatal week but declines thereafter, transitioning to fibrotic remodeling.
• The shift from regeneration to fibrosis involves changes in immune cell signaling, particularly macrophages, and cardiac fibroblasts (CFs).
• Molecular mechanisms driving age-dependent fibrosis and inflammation post-myocardial infarction (MI) remain poorly understood.

Purpose of the Study:

• To elucidate the distinct contributions of cardiac fibroblasts and macrophages in heart healing during regenerative and non-regenerative phases.
• To identify molecular pathways and cellular responses that differentiate neonatal regenerative hearts from older, non-regenerative hearts after MI.
• To understand how age-related immune shifts, specifically macrophage ontogeny, impact cardiac repair and regeneration.

Main Methods:

• Analysis of bulk RNA sequencing (RNA-Seq) datasets from neonatal (regenerative) and adult (non-regenerative) mouse myocardium and cardiac fibroblasts.
• Single-cell RNA-Seq analysis of cardiac macrophages from hearts at different postnatal ages.
• Comparative pathway analysis to identify MI-specific differences between regenerative and non-regenerative hearts.

Main Results:

• Non-regenerative hearts exhibited increased extracellular matrix (ECM) production, heightened matricellular signaling, and elevated inflammation post-MI compared to neonates.
• Older hearts showed greater chemotactic gradients for macrophage recruitment and higher expression of danger-associated molecular pattern (DAMP) receptors.
• Key inflammatory pathways, including NF-κB and AP-1 signaling, were upregulated in non-regenerative hearts, initiating profibrotic gene programs by day 3 post-MI.

Conclusions:

• The ontogenetic shift in cardiac macrophages postnatally contributes to detrimental stress signaling that suppresses heart regeneration.
• Upregulated sterile inflammatory processes in non-regenerative hearts initiate profibrotic gene programs, leading to fibrosis and impaired repair.
• Understanding these age-dependent immune and cellular mechanisms is crucial for developing strategies to promote cardiac regeneration.