Chalcone-Supported Cardiac Mesoderm Induction in Human Pluripotent Stem Cells for Heart Muscle Engineering

Area of Science:

• Cardiovascular Research
• Stem Cell Biology
• Drug Discovery

Background:

• Human pluripotent stem cells (hPSCs) are crucial for cardiovascular research, cell therapy, and drug screening.
• Bone morphogenetic protein 4 (BMP4) is essential for inducing cardiac mesoderm and deriving cardiomyocytes from hPSCs.
• Standardizing cardiomyocyte derivation is vital for reproducible research and therapeutic applications.

Purpose of the Study:

• To explore chalcones as small-molecule Bone morphogenetic protein 4 (BMP4) mimetics for cardiac mesoderm induction.
• To evaluate the efficacy of chalcones in deriving cardiomyocytes from hPSCs.
• To assess the potential of derived cardiomyocytes in forming contractile engineered human myocardium (EHM).

Main Methods:

• A two-tiered screening strategy was employed, involving directed differentiation of hPSCs with various chalcones.
• Commercial chalcones (4 ahydroxychalcone [4'HC], Isoliquiritigen) and 24 novel derivatives were tested.
• A functional screen assessed the self-organization of derived cardiomyocytes into EHM.

Main Results:

• Three chalcones, including 4'HC, demonstrated effectiveness in cardiac mesoderm induction.
• 4'-fluoro-4'-methoxychalcone and 4'-fluoro-4'-hydroxychalcone showed comparable induction to 4'HC.
• Only 4'HC successfully replaced BMP4 in deriving cardiomyocytes capable of forming contractile EHM.

Conclusions:

• Chalcones, particularly 4'HC, can effectively induce cardiac mesoderm from hPSCs.
• 4'HC serves as a functional BMP4 mimetic for deriving contractile EHM-forming cardiomyocytes.
• Chalcone-based strategies offer a promising avenue for standardized cardiomyocyte generation in cardiovascular research.