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Serum supplemented culture medium masks hypertrophic phenotypes in human pluripotent stem cell derived cardiomyocytes
Cheryl Dambrot1, Stefan R Braam, Leon G J Tertoolen
1Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
Insights
Fetal calf serum can mask hypertrophic effects in human pluripotent stem cell-derived cardiomyocytes, potentially underestimating drug and gene mutation impacts. Researchers recommend using low-serum conditions to accurately assess cardiac phenotypes.
Area of Science:
- Cardiology
- Stem Cell Biology
- Molecular Cardiology
Background:
- Fetal calf serum (FCS) is known to induce hypertrophy in cultured cardiomyocytes.
- This effect is often overlooked in studies using cardiomyocytes derived from pluripotent stem cells (PSCs).
- Understanding serum's impact is crucial for accurate phenotype assessment in PSC-derived models.
Purpose of the Study:
- To investigate the effects of serum on human embryonic stem cell (hESC)- and induced pluripotent stem cell (hiPSC)-derived cardiomyocytes.
- To determine if serum masks the hypertrophic effects of gene mutations (MYBPC3) and drugs (phenylephrine) in these cells.
Main Methods:
- Cultured neonatal rat cardiomyocytes to confirm known serum effects.
- Assessed cell surface area and beating frequency of hESC- and hiPSC-derived cardiomyocytes with and without serum.
- Evaluated the impact of phenylephrine and MYBPC3 gene mutation on cardiomyocyte phenotype under serum conditions.
Main Results:
- Serum increased cell surface area and spontaneous contraction rate in hESC- and hiPSC-derived cardiomyocytes.
- Phenylephrine did not induce additional hypertrophy in the presence of serum.
- Serum abolished the genotype-predicted increased cell surface area in hiPSC-derived cardiomyocytes from MYBPC3 patients.
Conclusions:
- Serum significantly alters the phenotype of human PSC-derived cardiomyocytes, masking drug and genetic mutation effects.
- The presence of serum can lead to underestimation of cardiac hypertrophy.
- Cardiac phenotypes should be examined in low-serum or serum-free media for accurate assessment.
Abstract:
It has been known for over 20 years that foetal calf serum can induce hypertrophy in cultured cardiomyocytes but this is rarely considered when examining cardiomyocytes derived from pluripotent stem cells (PSC). Here, we determined how serum affected cardiomyocytes from human embryonic- (hESC) and induced pluripotent stem cells (hiPSC) and hiPSC from patients with hypertrophic cardiomyopathy linked to a mutation in the MYBPC3 gene. We first confirmed previously published hypertrophic effects of serum on cultured neonatal rat cardiomyocytes demonstrated as increased cell surface area and beating frequency. We then found that serum increased the cell surface area of hESC- and hiPSC-derived cardiomyocytes and their spontaneous contraction rate. Phenylephrine, which normally induces cardiac hypertrophy, had no additional effects under serum conditions. Likewise, hiPSC-derived cardiomyocytes from three MYBPC3 patients which had a greater surface area than controls in the absence of serum as predicted by their genotype, did not show this difference in the presence of serum. Serum can thus alter the phenotype of human PSC derived cardiomyocytes under otherwise defined conditions such that the effects of hypertrophic drugs and gene mutations are underestimated. It is therefore pertinent to examine cardiac phenotypes in culture media without or in low concentrations of serum.
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