Patient-Derived 3D Bioprinted Cardiac Organoid Constructs Reveal Key Pathological Features of Duchenne Muscular...

Area of Science:

• Cardiovascular Research
• Regenerative Medicine
• Genetics

Background:

• Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration, with cardiomyopathy being the primary cause of death.
• Current models lack reliability in elucidating DMD cardiomyopathy's exact pathogenic mechanisms.
• Key hallmarks include calcium dysregulation, fibrosis, and fat deposits, but underlying processes are unclear.

Purpose of the Study:

• To develop and validate 3D cardiac organoids (COs) and bioprinted cardiac constructs (bCOs) from DMD patient-derived induced pluripotent stem cells (DMD-hiPSCs).
• To investigate the utility of these models in recapitulating DMD-associated cardiomyopathy.
• To establish advanced tools for studying DMD cardiomyopathy and facilitating drug screening.

Main Methods:

• Generation of 3D cardiac organoids (COs) from DMD-hiPSCs, isogenic controls (DMD-Iso-hiPSCs), and healthy controls (HC-hiPSCs).
• Cardiac differentiation and characterization of COs for disease-specific features.
• Bioprinting of COs into hydrogel constructs (bCOs) using alginate-gelatin.
• Assessment of bCOs for cell death, gene expression, and markers of cardiac and fibrotic pathology.

Main Results:

• DMD-COs exhibited increased cell death, elevated ROS, and calcium signaling defects compared to controls.
• Bioprinted constructs (bCOs) showed enhanced cell-cell communication and reduced NKX2.5 levels.
• DMD-bCOs recapitulated key features of DMD cardiomyopathy, including increased cell death and dysregulated cardiac/fibrotic markers.

Conclusions:

• 3D cardiac organoids and bioprinted constructs derived from DMD-hiPSCs serve as reliable models for DMD cardiomyopathy.
• These advanced models offer significant potential for understanding disease mechanisms.
• The developed COs and bCOs can advance drug screening and therapeutic development for DMD.