Section of Diabetes and Endocrinology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Department of Gynecology and Obstetrics, The First Affiliated Hospital of Fujian Medical University, Fu Zhou, China.
Stem Cells Dev. 2023 Mar;32(5-6):131-139. doi: 10.1089/scd.2022.0226. Epub 2023 Feb 13.
Adverse intrauterine environments can cause persistent changes in epigenetic profiles of stem cells, increasing susceptibility of the offspring to developing metabolic diseases later in life. Effective approaches to restore the epigenetic landscape and function of stem cells remain to be determined. In this study, we investigated the effects of pharmaceutical activation of AMP-activated protein kinase (AMPK), an essential regulator of energy metabolism, on mitochondrial programming of Wharton's Jelly mesenchymal stem cells (WJ-MSCs) from women with diabetes during pregnancy. Induction of myogenic differentiation of WJ-MSCs was associated with increased proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression and mitochondrial DNA (mtDNA) abundance. Inhibition of DNA methylation by 5 Azacytidine significantly increased PGC-1α expression and mtDNA abundance in WJ-MSCs, which were abolished by AMPK inhibitor Compound C (CC), suggesting an AMPK-dependent role of DNA demethylation in regulating mitochondrial biogenesis in WJ-MSCs. Furthermore, activation of AMPK in diabetic WJ-MSCs by AICAR or metformin decreased the level of PGC-1α promoter methylation and increased PGC-1α expression. Notably, decreased PGC-1α promoter methylation by transient treatment of AMPK activators persisted after myogenic differentiation. This was associated with enhanced myogenic differentiation capacity of human WJ-MSCs and increased mitochondrial function. Taken together, our findings revealed an important role for AMPK activators in epigenetic regulation of mitochondrial biogenesis and myogenesis in WJ-MSCs, which could lead to potential therapeutics for preventing fetal mitochondrial programming and long-term adverse outcome in offspring of women with diabetes during pregnancy.
不利的宫内环境会导致干细胞表观遗传谱发生持久变化，增加后代在以后的生活中患上代谢性疾病的易感性。目前仍需要确定有效方法来恢复干细胞的表观遗传景观和功能。在这项研究中，我们研究了在怀孕期间患有糖尿病的女性的沃顿胶间充质干细胞（WJ-MSCs）中，药物激活 AMP 激活的蛋白激酶（AMPK），一种能量代谢的必需调节剂，对其线粒体编程的影响。WJ-MSCs 的成肌分化诱导与增殖物激活受体-γ共激活因子-1α（PGC-1α）表达和线粒体 DNA（mtDNA）丰度增加有关。5-氮杂胞苷抑制 DNA 甲基化可显著增加 WJ-MSCs 中的 PGC-1α表达和 mtDNA 丰度，而 AMPK 抑制剂 Compound C（CC）则消除了这种作用，提示 DNA 去甲基化在调节 WJ-MSCs 中线粒体生物发生中具有 AMPK 依赖性。此外，AICAR 或二甲双胍激活糖尿病 WJ-MSCs 中的 AMPK 可降低 PGC-1α启动子甲基化水平并增加 PGC-1α表达。值得注意的是，AMPK 激活剂短暂处理降低 PGC-1α启动子甲基化的作用在成肌分化后仍然存在。这与人类 WJ-MSCs 的成肌分化能力增强和线粒体功能增加有关。总之，我们的研究结果揭示了 AMPK 激活剂在 WJ-MSCs 中线粒体生物发生和肌发生的表观遗传调控中的重要作用，这可能为预防糖尿病孕妇胎儿线粒体编程和后代长期不良结局提供潜在的治疗方法。
