Co-culturing hiPSC-cardiomyocytes and cardiac fibroblasts enhances engineered heart tissue structure and function

Area of Science:

• Cardiovascular Research
• Stem Cell Biology
• Tissue Engineering

Background:

• Engineered heart tissues (EHTs) are crucial for cardiac disease modeling and drug screening.
• Current EHTs often lack multicellularity, limiting their translational relevance.
• Incorporating diverse cardiac cell types is essential for improving EHT model accuracy and reliability.

Purpose of the Study:

• To develop a co-culture EHT model using human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and cardiac fibroblasts (CFs).
• To comprehensively assess the structural, contractile, electrophysiological, and metabolic characteristics of the developed co-culture EHTs.
• To compare the properties of co-culture EHTs against CM-only EHTs.

Main Methods:

• hiPSCs were differentiated into CMs and CFs.
• Co-culture EHTs were generated by combining hiPSC-CMs and hiPSC-CFs at a 3:1 ratio.
• Structural, functional, and metabolic assessments were performed using immunofluorescence, force analysis, optical mapping, and metabolomics.

Main Results:

• Co-culture EHTs exhibited enhanced compactness and generated greater contractile force compared to CM-only EHTs.
• Improved sarcomere organization and reduced hypoxia under high-frequency pacing were observed in co-culture EHTs.
• Co-culture EHTs demonstrated a more mature, stress-resistant metabolic profile with stable electrophysiology and reduced arrhythmogenicity.

Conclusions:

• The integration of hiPSC-CFs significantly enhances the structural and functional attributes of EHTs.
• Co-culture EHTs provide improved stress resistance and reduced variability, leading to a more predictive experimental model.
• This multicellular EHT platform offers a more physiological and accurate system for cardiac disease modeling and drug discovery.