Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Santariškių 5, LT-08406 Vilnius, Lithuania.
Myomedix Ltd., Im Biengarten 36, 69151 Neckargemuend, Germany.
Int J Mol Sci. 2024 Jun 19;25(12):6758. doi: 10.3390/ijms25126758.
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.
扩张型心肌病（DCM）的患病率在全球范围内不断增加，这凸显了需要创新的治疗方法来预防其发生。在这项研究中，我们研究了扩张型和非扩张型人心肌源性间充质干细胞（hmMSC）之间的能量和表观遗传差异，并评估了 I 类和 II 类组蛋白去乙酰化酶抑制剂（HDACi）对这些细胞及其心肌生成分化的影响。使用组织块培养方法从心肌活检中分离细胞。使用流式细胞术、PCR、化学发光、Western blot 和免疫组织化学评估线粒体和组蛋白去乙酰化酶活性、ATP 水平、心脏转录因子和结构蛋白。数据表明，所测试的 HDAC 抑制剂改善了两种细胞的乙酰化并增强了其能量状态，在扩张型心肌源性 hmMSC 中观察到显著效果。此外，HDAC 抑制剂激活了心脏转录因子 Nkx2-5、HOPX、GATA4 和 Mef2C，并在蛋白和基因水平上调了结构蛋白，如心肌肌钙蛋白 T 和α-心肌肌动蛋白。总之，我们的研究结果表明，HDACi 可能作为人类心脏 hmMSC 能量状态和心肌生成分化的潜在调节剂。这一探索途径可能会扩大对扩张型心肌病新型治疗干预措施的研究，最终改善心脏功能。
