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Updated: Apr 20, 2026
Generation and Expansion of Human Cardiomyocytes from Patient Peripheral Blood Mononuclear Cells
Published on: February 12, 2021
Aberrant α-adrenergic hypertrophic response in cardiomyocytes from human induced pluripotent cells
Gabor Földes1, Elena Matsa2, János Kriston-Vizi3
1National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; Heart and Vascular Center, Semmelweis University, Budapest H1122, Hungary.
Insights
Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) respond to hypertrophic signals, unlike induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). This unresponsiveness in hiPSC-CMs is due to suppressed growth pathways, limiting their use in cardiac disease research.
Area of Science:
- Cardiology
- Stem Cell Biology
- Drug Discovery
Background:
- Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are valuable models for drug discovery.
- Cardiac hypertrophy is a significant pathological process and a key target for therapeutic intervention.
Purpose of the Study:
- To investigate the differential responsiveness of hESC-CMs and hiPSC-CMs to hypertrophic stimuli.
- To elucidate the underlying molecular mechanisms responsible for the observed unresponsiveness in hiPSC-CMs.
Main Methods:
- Comparative analysis of cardiomyocyte responses to hypertrophic agonists like phenylephrine.
- Gene expression profiling to assess adrenergic receptor (αAR) gene expression (ADRA1A, ADRA1B).
- Investigation of intracellular signaling pathways, including inhibitory kinase activity.
Main Results:
- hiPSC-CMs exhibited systematic unresponsiveness to hypertrophic signals compared to hESC-CMs.
- ADRA1A gene expression was silenced during hiPSC differentiation, with compensatory ADRA1B upregulation.
- ADRA1B signaling was functional in hESC-CMs but impaired in hiPSC-CMs.
- hiPSC-CMs displayed increased tonic activity in inhibitory kinase pathways, suppressing cell growth.
Conclusions:
- Tonic suppression of growth pathways in hiPSC-CMs limits their utility as models for studying hypertrophic signaling.
- The findings raise concerns about the validity of hiPSC-CMs for specific cardiac disease research, particularly concerning hypertrophy.
- Further research is needed to optimize hiPSC-CM differentiation or identify alternative models for studying cardiac hypertrophy.
Abstract:
Cardiomyocytes from human embryonic stem cells (hESC-CMs) and induced pluripotent stem cells (hiPSC-CMs) represent new models for drug discovery. Although hypertrophy is a high-priority target, we found that hiPSC-CMs were systematically unresponsive to hypertrophic signals such as the α-adrenoceptor (αAR) agonist phenylephrine (PE) compared to hESC-CMs. We investigated signaling at multiple levels to understand the underlying mechanism of this differential responsiveness. The expression of the normal α1AR gene, ADRA1A, was reversibly silenced during differentiation, accompanied by ADRA1B upregulation in either cell type. ADRA1B signaling was intact in hESC-CMs, but not in hiPSC-CMs. We observed an increased tonic activity of inhibitory kinase pathways in hiPSC-CMs, and inhibition of antihypertrophic kinases revealed hypertrophic increases. There is tonic suppression of cell growth in hiPSC-CMs, but not hESC-CMs, limiting their use in investigation of hypertrophic signaling. These data raise questions regarding the hiPSC-CM as a valid model for certain aspects of cardiac disease.
