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Updated: May 4, 2026
Enhancing the Engraftment of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes via a Transient Inhibition of Rho Kinase Activity
Published on: July 10, 2019
PGC-1α and reactive oxygen species regulate human embryonic stem cell-derived cardiomyocyte function
Matthew J Birket1, Simona Casini1, Georgios Kosmidis1
1Leiden University Medical Center, 2300RC Leiden, The Netherlands.
Abstract:
Diminished mitochondrial function is causally related to some heart diseases. Here, we developed a human disease model based on cardiomyocytes from human embryonic stem cells (hESCs), in which an important pathway of mitochondrial gene expression was inactivated. Repression of PGC-1α, which is normally induced during development of cardiomyocytes, decreased mitochondrial content and activity and decreased the capacity for coping with energetic stress. Yet, concurrently, reactive oxygen species (ROS) levels were lowered, and the amplitude of the action potential and the maximum amplitude of the calcium transient were in fact increased. Importantly, in control cardiomyocytes, lowering ROS levels emulated this beneficial effect of PGC-1α knockdown and similarly increased the calcium transient amplitude. Our results suggest that controlling ROS levels may be of key physiological importance for recapitulating mature cardiomyocyte phenotypes, and the combination of bioassays used in this study may have broad application in the analysis of cardiac physiology pertaining to disease.
Insights
Repressing PGC-1α in human heart cells reduced mitochondrial function but lowered reactive oxygen species (ROS). This surprising finding suggests controlling ROS is key for mature heart cell function and treating heart disease.
Area of Science:
- Biochemistry
- Cardiology
- Stem Cell Biology
Background:
- Mitochondrial dysfunction is linked to heart disease.
- PGC-1α is crucial for mitochondrial gene expression in cardiomyocytes.
Purpose of the Study:
- To investigate the role of PGC-1α in cardiomyocyte function using a human disease model.
- To explore the relationship between PGC-1α, mitochondrial activity, and reactive oxygen species (ROS).
Main Methods:
- Developed a human disease model using cardiomyocytes derived from human embryonic stem cells (hESCs).
- Inactivated a key mitochondrial gene expression pathway by repressing PGC-1α.
- Measured mitochondrial content, activity, ROS levels, action potential, and calcium transients.
Main Results:
- Repressing PGC-1α decreased mitochondrial content and activity, impairing energetic stress response.
- Concurrently, reactive oxygen species (ROS) levels were reduced.
- Lowering ROS in control cells mimicked PGC-1α repression effects, increasing calcium transient amplitude.
Conclusions:
- Controlling ROS levels is critical for achieving mature cardiomyocyte phenotypes.
- The developed hESC-derived cardiomyocyte model and bioassays are valuable for studying cardiac physiology and disease.
- Targeting ROS may offer therapeutic strategies for heart diseases linked to mitochondrial dysfunction.
