Decoding Fibroblast Diversity Associated with the Postnatal Loss of Cardiac Regenerative Capacity

Area of Science:

• Cardiovascular Biology
• Cellular and Molecular Medicine
• Regenerative Medicine

Background:

• Mammalian heart regeneration capacity diminishes post-birth, leading to scar formation and fibrosis after myocardial infarction (MI).
• Cardiac fibroblasts (CFs) are key in extracellular matrix (ECM) remodeling, but their age-dependent heterogeneity and communication networks remain unclear.

Purpose of the Study:

• To investigate age-dependent differences in cardiac fibroblast heterogeneity and communication networks between neonatal and adult mouse hearts.
• To understand how these differences contribute to the distinct regenerative capacities of neonatal versus adult hearts following injury.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of nonmyocyte cells from neonatal (P3) and adult (P84) mouse hearts.
• Identification and characterization of cardiac fibroblast subclusters (CF0-CF4) based on transcriptional profiles.
• Analysis of ECM composition using matrisome scoring and cell-cell communication via ligand-receptor inference (CellChat).

Main Results:

• Five distinct CF subclusters were identified with age-specific distributions and functional programs (e.g., immune, ECM structural, contractile, Wnt-modulating, proliferative).
• Neonatal CFs showed higher enrichment in core ECM components, while adult CFs were enriched in ECM regulators; adult CF communication networks were weaker and dominated by immune pathways.
• Post-MI analysis showed adult injury partially activated neonatal-like programs but lacked a specific Wnt-modulating program found in neonatal injury.

Conclusions:

• Age-dependent divergence in CF states, ECM specialization, and communication networks distinguishes regenerative neonatal from non-regenerative adult hearts.
• Findings provide a framework for interpreting stromal responses to MI and prioritizing CF programs for regenerative and anti-fibrotic therapies.