Dynamic Interstitial Cell Response during Myocardial Infarction Predicts Resilience to Rupture in Genetically Diverse...

Area of Science:

• Cardiovascular Biology
• Regenerative Medicine
• Single-cell Genomics

Background:

• Cardiac ischemia causes myocardial tissue loss, initiating scar formation.
• Scar characteristics influence healing outcomes, from favorable repair to detrimental cardiac rupture.
• Epicardial-derived cells contribute to the cardiac interstitium and scar development.

Purpose of the Study:

• To identify and characterize cellular subtypes involved in cardiac scar formation post-infarction.
• To investigate the cellular and molecular differences in scar development between mouse strains with divergent rupture frequencies.
• To define early cellular events that predict pathological cardiac remodeling and rupture.

Main Methods:

• Unbiased single-cell mRNA sequencing of interstitial cells from infarcted mouse hearts.
• Utilized a genetic tracer to identify epicardial-derived cells within the cardiac interstitium.
• Comparative transcriptomic analysis of post-infarction hearts from C57BL/6J and 129S1/SvImJ inbred mice.

Main Results:

• Identified 16 interstitial cell clusters, including 5 of epicardial origin.
• Defined 11 sub-clusters of stromal cells, revealing diverse fibroblast states (epicardial- and endocardial-derived).
• Observed an early increase in activated myofibroblasts, enhanced collagen deposition, and persistent acute phase response in 129S1/SvImJ mice, correlating with higher rupture rates.

Conclusions:

• Epicardial-derived fibroblasts represent a significant and diverse cellular component of the cardiac scar.
• Early post-infarction cellular dynamics, particularly myofibroblast activation and inflammatory responses, are critical determinants of cardiac rupture susceptibility.
• Transcriptomic profiling of distinct interstitial cell populations provides insights into pathological remodeling and potential therapeutic targets for post-myocardial infarction complications.