Modeling Hypoxic Stress In Vitro Using Human Embryonic Stem Cells Derived Cardiomyocytes Matured by FGF4 and Ascorbic...

Area of Science:

• Cardiovascular Biology
• Stem Cell Biology
• Regenerative Medicine

Background:

• Mature cardiomyocytes are crucial for modeling adult-onset cardiac diseases and drug discovery.
• Human pluripotent stem cells (hPSCs) offer a promising source for generating patient-specific cardiomyocytes.
• Existing methods for cardiomyocyte maturation require optimization for disease modeling.

Purpose of the Study:

• To investigate the efficacy of FGF4 and ascorbic acid (AA) in inducing maturation of hPSC-derived cardiomyocytes (hESC-CMCs).
• To establish an in vitro model for studying hypoxic stress and acute myocardial infarction (AMI) using matured hESC-CMCs.
• To identify hypoxia-responsive genes and potential cardiac biomarkers in matured hESC-CMCs.

Main Methods:

• BG01 human embryonic stem cell-cardiogenic mesoderm cells (hESC-CMCs) were treated with FGF4 and AA.
• Differentiation and maturation of hESC-CMCs were assessed.
• Matured hESC-CMCs were subjected to hypoxic injury.
• Release of AMI biomarkers (cTnI, CK-MB, myoglobin) was measured.
• Transcriptome analysis was performed to identify hypoxia-responsive genes.

Main Results:

• Co-treatment with FGF4 and AA synergistically induced differentiation into mature and ventricular CMs.
• FGF4+AA-treated hESC-CMCs robustly released AMI biomarkers in response to hypoxic injury.
• Transcriptome analysis revealed induction of hypoxia-responsive genes and potential cardiac biomarkers in response to hypoxia.
• The study successfully demonstrated the feasibility of in vitro hypoxic stress modeling.

Conclusions:

• FGF4 and AA are effective soluble factors for maturing hESC-CMCs into functional ventricular cardiomyocytes.
• Matured hESC-CMCs provide a robust in vitro model for studying hypoxic cardiac injury and AMI.
• This model facilitates the discovery of novel cardiac biomarkers and therapeutic targets for coronary artery diseases.