Short-Term DMOG treatment rejuvenates senescent mesenchymal stem cells by enhancing mitochondrial function and mitophagy through the HIF-1α/BNIP3 pathway

作者：Jiaxin Wen, Lingxian Yi, Lei Chen, Jingjing Xu, Yanmin Zhang, Qiheng Cheng, Hangyu Ping, Huanyu Wang, Feng Shuang, Wei Chai, Tujun Weng · 发表于：Stem Cell Research & Therapy · 年份：2025 · DOI：10.1186/s13287-025-04422-2 · 被引用次数：13 · 研究领域：Mesenchymal stem cell research、Telomeres, Telomerase, and Senescence、Autophagy in Disease and Therapy

BACKGROUND: Mesenchymal stem cells (MSCs) have potential for treating degenerative and immune diseases, but their clinical efficacy is limited by senescence, characterized by mitochondrial dysfunction, impaired mitophagy, and metabolic imbalance. The goal of this study was to investigate the effects of dimethyloxalylglycine (DMOG), a hypoxia-mimetic agent that stabilizes hypoxia-inducible factor 1 alpha (HIF-1α), on rejuvenating senescent MSCs by enhancing mitochondrial function, mitophagy, and metabolic reprogramming. METHODS: Two models of MSC senescence were established: oxidative stress-induced senescence using hydrogen peroxide and replicative senescence through serial passaging. Umbilical cord derived MSCs were treated with DMOG for 48 h under normoxic conditions. Mitochondrial function, mitophagy, and metabolism were assessed using assays that measured mitochondrial membrane potential, reactive oxygen species levels, ATP production, and mitophagy. Western blotting and real-time PCR were employed to analyze the expression changes of relevant molecules. RNA sequencing (RNA-seq) was performed to identify key genes and pathways regulated by DMOG. Additionally, to evaluate the therapeutic potential of rejuvenated MSCs, a co-culture system was established, where DMOG-treated senescent MSCs were co-cultured with IL-1β-treated chondrocytes. RESULTS: DMOG treatment significantly reduced key senescence markers, including senescence-associated beta-galactosidase, p53, and p21, in...