Topological Arrangement of Cardiac Fibroblasts Regulates Cellular Plasticity

Area of Science:

• Cardiovascular Biology
• Cellular Biology
• Biomedical Engineering

Background:

• Cardiac fibroblasts reside in the interstitium between myocytes, maintaining a specific topological relationship.
• Following acute myocardial injury, fibroblasts aggregate in necrotic regions, a unique event with poorly understood functional consequences.

Purpose of the Study:

• To investigate how altered topological states of cardiac fibroblasts, particularly after injury, affect their cellular phenotype.
• To understand the molecular mechanisms underlying fibroblast behavior changes in response to topological shifts.

Main Methods:

• Utilized 2D and 3D cell culture models to simulate different fibroblast topological states.
• Employed genome-wide gene expression analysis and chromatin remodeling assays.
• Applied tissue clearing techniques for in vivo scar tissue visualization.
• Used quantitative phase microscopy (live cell interferometry) to measure cell biomass changes.

Main Results:

• Simple fibroblast aggregation in 3D culture induced genome-wide gene expression changes and chromatin remodeling.
• These gene expression alterations were reversible upon returning to a 2D state, indicating topological regulation of cellular plasticity.
• Genes upregulated by fibroblast aggregation predicted adverse cardiac remodeling in mouse models.
• Fibroblasts in dense scar tissue exhibited gene expression patterns similar to those in 3D culture.
• Conditioned medium from 3D-cultured fibroblasts promoted cardiomyocyte hypertrophy.

Conclusions:

• Topological changes in cardiac fibroblast organization are sufficient to drive significant chromatin remodeling and global gene expression shifts.
• These fibroblast-driven changes have functional implications for cardiac repair and healing processes.
• The study reveals a novel layer of cellular regulation based on physical organization with potential relevance to heart disease progression.