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Updated: Jun 22, 2025
Evaluation of Cardiac Contractility Modulation Therapy in 2D Human Stem Cell-Derived Cardiomyocytes
Published on: December 16, 2022
Class I and II Histone Deacetylase Inhibitors as Therapeutic Modulators of Dilated Cardiac Tissue-Derived Mesenchymal
Rokas Mikšiūnas1, Siegfried Labeit2, Daiva Bironaite1
1Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Santariškių 5, LT-08406 Vilnius, Lithuania.
Insights
Histone deacetylase inhibitors (HDACi) improved the energy status and acetylation in human heart stem cells. These findings suggest HDACi may offer new therapeutic strategies for dilated cardiomyopathy (DCM).
Area of Science:
- Cardiovascular Biology
- Stem Cell Biology
- Epigenetics
Background:
- Dilated cardiomyopathy (DCM) prevalence is rising globally, necessitating novel therapeutic strategies.
- Human myocardium-derived mesenchymal stem/stromal cells (hmMSCs) present a potential cell source for cardiac repair.
- Understanding energetic and epigenetic differences in hmMSCs from dilated vs. non-dilated hearts is crucial.
Purpose of the Study:
- To investigate energetic and epigenetic distinctions between hmMSCs from dilated and non-dilated human hearts.
- To assess the impact of class I and II histone deacetylase inhibitors (HDACi) on hmMSCs.
- To evaluate the effect of HDACi on cardiomyogenic differentiation of hmMSCs.
Main Methods:
- Isolation of hmMSCs from myocardial biopsies via explant outgrowth.
- Assessment of mitochondrial and histone deacetylase activities, ATP levels, and cardiac transcription factors.
- Analysis of protein and gene expression of cardiac structural proteins using flow cytometry, PCR, chemiluminescence, Western blotting, and immunohistochemistry.
Main Results:
- HDAC inhibitors enhanced acetylation and improved the energetic status of hmMSCs, particularly those from dilated hearts.
- HDACi treatment upregulated cardiac transcription factors (Nkx2-5, HOPX, GATA4, Mef2C) and structural proteins (cardiac troponin T, alpha cardiac actin).
- Effects were observed at both the protein and gene expression levels.
Conclusions:
- HDAC inhibitors show potential as modulators of hmMSC energetic status and cardiomyogenic differentiation.
- HDACi may represent a novel therapeutic avenue for dilated cardiomyopathy.
- Further research into HDACi could lead to improved treatments for heart failure and enhanced cardiac function.
Abstract:
The prevalence of dilated cardiomyopathy (DCM) is increasing globally, highlighting the need for innovative therapeutic approaches to prevent its onset. In this study, we examined the energetic and epigenetic distinctions between dilated and non-dilated human myocardium-derived mesenchymal stem/stromal cells (hmMSCs) and assessed the effects of class I and II HDAC inhibitors (HDACi) on these cells and their cardiomyogenic differentiation. Cells were isolated from myocardium biopsies using explant outgrowth methods. Mitochondrial and histone deacetylase activities, ATP levels, cardiac transcription factors, and structural proteins were assessed using flow cytometry, PCR, chemiluminescence, Western blotting, and immunohistochemistry. The data suggest that the tested HDAC inhibitors improved acetylation and enhanced the energetic status of both types of cells, with significant effects observed in dilated myocardium-derived hmMSCs. Additionally, the HDAC inhibitors activated the cardiac transcription factors Nkx2-5, HOPX, GATA4, and Mef2C, and upregulated structural proteins such as cardiac troponin T and alpha cardiac actin at both the protein and gene levels. In conclusion, our findings suggest that HDACi may serve as potential modulators of the energetic status and cardiomyogenic differentiation of human heart hmMSCs. This avenue of exploration could broaden the search for novel therapeutic interventions for dilated cardiomyopathy, ultimately leading to improvements in heart function.
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