Short-Term DMOG treatment rejuvenates senescent mesenchymal stem cells by enhancing mitochondrial function and mitophagy through the HIF-1α/BNIP3 pathway
Abstract 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...
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BMC
2025-06-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-025-04422-2 |
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| author | Jiaxin Wen Lingxian Yi Lei Chen Jinhan Xu Yanmin Zhang Qiheng Cheng Hangyu Ping Huanyu Wang Feng Shuang Wei Chai Tujun Weng |
| author_facet | Jiaxin Wen Lingxian Yi Lei Chen Jinhan Xu Yanmin Zhang Qiheng Cheng Hangyu Ping Huanyu Wang Feng Shuang Wei Chai Tujun Weng |
| author_sort | Jiaxin Wen |
| collection | DOAJ |
| description | Abstract 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 both senescence models. DMOG treatment restored mitochondrial morphology and function, improving mitochondrial membrane potential, reducing mitochondrial reactive oxygen species, and enhancing ATP production. DMOG also promoted mitophagy, as evidenced by increased colocalization of mitochondria with lysosomes. RNA-seq analysis revealed that DMOG activated key pathways, including HIF-1 signaling, calcium signaling, and mitophagy-related gene (BNIP3 and BNIP3L). Notably, BNIP3 knockdown greatly abolished DMOG-induced mitophagy and its anti-senescence effects. Furthermore, DMOG treatment improved metabolic flexibility by enhancing both mitochondrial respiration and glycolysis in senescent MSCs. Moreover, DMOG-treated senescent MSCs partially restored their therapeutic efficacy in an osteoarthritis model by improving extracellular matrix regulation in IL-1β-stimulated chondrocytes. Conclusions Short-term DMOG treatment rejuvenates senescent MSCs by enhancing mitochondrial function, promoting mitophagy via HIF-1α/BNIP3, and improving metabolic reprogramming. DMOG-treated MSCs also showed enhanced therapeutic efficacy in co-culture with IL-1β-treated chondrocytes, suggesting its potential to improve MSC-based therapies in regenerative medicine. |
| format | Article |
| id | doaj-art-5d812d46b4c94667a9a4afcb58e7f3aa |
| institution | Kabale University |
| issn | 1757-6512 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
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| series | Stem Cell Research & Therapy |
| spelling | doaj-art-5d812d46b4c94667a9a4afcb58e7f3aa2025-08-20T03:25:12ZengBMCStem Cell Research & Therapy1757-65122025-06-0116111710.1186/s13287-025-04422-2Short-Term DMOG treatment rejuvenates senescent mesenchymal stem cells by enhancing mitochondrial function and mitophagy through the HIF-1α/BNIP3 pathwayJiaxin Wen0Lingxian Yi1Lei Chen2Jinhan Xu3Yanmin Zhang4Qiheng Cheng5Hangyu Ping6Huanyu Wang7Feng Shuang8Wei Chai9Tujun Weng10Senior Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General HospitalDepartment of Emergency, The Ninth Medical Centre of Chinese PLA General HospitalSenior Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General HospitalSenior Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General HospitalSenior Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General HospitalSenior Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General HospitalSenior Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General HospitalSenior Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General HospitalDepartment of Orthopedics, The 908th Hospital of Joint Logistics Support Force of Chinese People’s Liberation ArmySenior Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General HospitalSenior Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General HospitalAbstract 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 both senescence models. DMOG treatment restored mitochondrial morphology and function, improving mitochondrial membrane potential, reducing mitochondrial reactive oxygen species, and enhancing ATP production. DMOG also promoted mitophagy, as evidenced by increased colocalization of mitochondria with lysosomes. RNA-seq analysis revealed that DMOG activated key pathways, including HIF-1 signaling, calcium signaling, and mitophagy-related gene (BNIP3 and BNIP3L). Notably, BNIP3 knockdown greatly abolished DMOG-induced mitophagy and its anti-senescence effects. Furthermore, DMOG treatment improved metabolic flexibility by enhancing both mitochondrial respiration and glycolysis in senescent MSCs. Moreover, DMOG-treated senescent MSCs partially restored their therapeutic efficacy in an osteoarthritis model by improving extracellular matrix regulation in IL-1β-stimulated chondrocytes. Conclusions Short-term DMOG treatment rejuvenates senescent MSCs by enhancing mitochondrial function, promoting mitophagy via HIF-1α/BNIP3, and improving metabolic reprogramming. DMOG-treated MSCs also showed enhanced therapeutic efficacy in co-culture with IL-1β-treated chondrocytes, suggesting its potential to improve MSC-based therapies in regenerative medicine.https://doi.org/10.1186/s13287-025-04422-2Mesenchymal stem cells (MSCs)SenescenceHypoxia-Mimetic agentHIF-1αBNIP3Mitophagy |
| spellingShingle | Jiaxin Wen Lingxian Yi Lei Chen Jinhan Xu Yanmin Zhang Qiheng Cheng Hangyu Ping Huanyu Wang Feng Shuang Wei Chai Tujun Weng Short-Term DMOG treatment rejuvenates senescent mesenchymal stem cells by enhancing mitochondrial function and mitophagy through the HIF-1α/BNIP3 pathway Stem Cell Research & Therapy Mesenchymal stem cells (MSCs) Senescence Hypoxia-Mimetic agent HIF-1α BNIP3 Mitophagy |
| title | Short-Term DMOG treatment rejuvenates senescent mesenchymal stem cells by enhancing mitochondrial function and mitophagy through the HIF-1α/BNIP3 pathway |
| title_full | Short-Term DMOG treatment rejuvenates senescent mesenchymal stem cells by enhancing mitochondrial function and mitophagy through the HIF-1α/BNIP3 pathway |
| title_fullStr | Short-Term DMOG treatment rejuvenates senescent mesenchymal stem cells by enhancing mitochondrial function and mitophagy through the HIF-1α/BNIP3 pathway |
| title_full_unstemmed | Short-Term DMOG treatment rejuvenates senescent mesenchymal stem cells by enhancing mitochondrial function and mitophagy through the HIF-1α/BNIP3 pathway |
| title_short | Short-Term DMOG treatment rejuvenates senescent mesenchymal stem cells by enhancing mitochondrial function and mitophagy through the HIF-1α/BNIP3 pathway |
| title_sort | short term dmog treatment rejuvenates senescent mesenchymal stem cells by enhancing mitochondrial function and mitophagy through the hif 1α bnip3 pathway |
| topic | Mesenchymal stem cells (MSCs) Senescence Hypoxia-Mimetic agent HIF-1α BNIP3 Mitophagy |
| url | https://doi.org/10.1186/s13287-025-04422-2 |
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