Single-Cell Reconstruction of Progression Trajectory Reveals Intervention Principles in Pathological Cardiac...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Single-cell Genomics

Background:

• Pathological cardiac hypertrophy precedes heart failure, a leading cause of cardiovascular mortality.
• Current treatments offer limited relief post-heart failure onset.
• Need for cell type- and stage-specific therapeutic strategies is critical.

Purpose of the Study:

• To analyze cell type dynamics and interactions during pressure overload-induced cardiac hypertrophy.
• To identify potential pharmacological targets for intervention.
• To validate findings in human cardiac disease samples.

Main Methods:

• Single-cell RNA sequencing of 11,492 cells from a mouse model of cardiac hypertrophy.
• Identification of major cardiac cell types and subtypes based on molecular signatures.
• In vivo testing of pharmacological interventions targeting identified cellular pathways.

Main Results:

• Detailed characterization of cardiomyocyte, endothelial, fibroblast, and macrophage dynamics during hypertrophy progression.
• Demonstrated stagewise crosstalk between cell types, with specific noncardiomyocyte roles.
• Macrophage activation and subtype switching identified as a key middle-stage event, successfully targeted by Dapagliflozin, TD139, and Arglabin to preserve cardiac function and attenuate fibrosis.
• Identified similar molecular patterns in human hypertrophic cardiomyopathy and heart failure samples.

Conclusions:

• The study elucidates dynamic cell-cell communication in pathological cardiac hypertrophy.
• Provides a basis for developing cell type- and stage-specific interventions for cardiac diseases.
• Highlights the therapeutic potential of targeting macrophage dynamics in heart conditions.