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Generation and Expansion of Human Cardiomyocytes from Patient Peripheral Blood Mononuclear Cells
Published on: February 12, 2021
Human ventricular unloading induces cardiomyocyte proliferation
Diana C Canseco1, Wataru Kimura1, Sonia Garg1
1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
Insights
Mechanical unloading of the adult heart reduces mitochondrial mass and DNA damage, promoting cardiomyocyte proliferation. This suggests a novel approach for cardiac regeneration by preventing cell cycle arrest.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Cellular Biology
Background:
- Adult mammalian hearts lack significant regenerative capacity due to cardiomyocyte cell cycle arrest.
- Mitochondria-mediated oxidative DNA damage is a known regulator of this arrest.
- The role of mechanical load in this process remained unexplored.
Purpose of the Study:
- To investigate the impact of mechanical unloading on mitochondrial mass, DNA damage response, and cardiomyocyte proliferation.
- To determine if reducing mechanical load can overcome cardiomyocyte cell cycle arrest.
Main Methods:
- Analysis of human ventricular samples before and after left ventricular assist device (LVAD) implantation.
- Quantification of mitochondrial content, DNA damage response markers (phosphorylated ataxia telangiectasia mutated), and cardiomyocyte proliferation markers (phosphorylated histone H3, Aurora B).
Main Results:
- Mechanical unloading led to a significant decrease in mitochondrial content (up to 60%) and cardiomyocyte size (up to 45%).
- A marked reduction in DNA damage response foci was observed post-LVAD.
- Increased cardiomyocyte mitosis and cytokinesis were evident, particularly with longer unloading durations.
Conclusions:
- Prolonged mechanical unloading promotes adult human cardiomyocyte proliferation.
- This proliferation may occur by preventing mitochondria-mediated activation of the DNA damage response.
- Mechanical unloading represents a potential strategy for cardiac regeneration.
Background:
The adult mammalian heart is incapable of meaningful regeneration after substantial cardiomyocyte loss, primarily due to the inability of adult cardiomyocytes to divide. Our group recently showed that mitochondria-mediated oxidative DNA damage is an important regulator of postnatal cardiomyocyte cell cycle arrest. However, it is not known whether mechanical load also plays a role in this process. We reasoned that the postnatal physiological increase in mechanical load contributes to the increase in mitochondrial content, with subsequent activation of DNA damage response (DDR) and permanent cell cycle arrest of cardiomyocytes.
Objectives:
The purpose of this study was to test the effect of mechanical unloading on mitochondrial mass, DDR, and cardiomyocyte proliferation.
Methods:
We examined the effect of human ventricular unloading after implantation of left ventricular assist devices (LVADs) on mitochondrial content, DDR, and cardiomyocyte proliferation in 10 matched left ventricular samples collected at the time of LVAD implantation (pre-LVAD) and at the time of explantation (post-LVAD).
Results:
We found that post-LVAD hearts showed up to a 60% decrease in mitochondrial content and up to a 45% decrease in cardiomyocyte size compared with pre-LVAD hearts. Moreover, we quantified cardiomyocyte nuclear foci of phosphorylated ataxia telangiectasia mutated protein, an upstream regulator of the DDR pathway, and we found a significant decrease in the number of nuclear phosphorylated ataxia telangiectasia mutated foci in the post-LVAD hearts. Finally, we examined cardiomyocyte mitosis and cytokinesis and found a statistically significant increase in both phosphorylated histone H3-positive, and Aurora B-positive cardiomyocytes in the post-LVAD hearts. Importantly, these results were driven by statistical significance in hearts exposed to longer durations of mechanical unloading.
Conclusions:
Prolonged mechanical unloading induces adult human cardiomyocyte proliferation, possibly through prevention of mitochondria-mediated activation of DDR.
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