MSC-sEVs exacerbate senescence by transferring bisecting GlcNAcylated GPNMB
Abstract Background The senescence of bone marrow mesenchymal stem cells (BMMSCs) is increasingly recognized as a critical factor contributing to the pathophysiology of age-related diseases. Recent studies suggest that small extracellular vesicles (sEVs) derived from the serum of elderly individuals...
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BMC
2025-01-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-025-04140-9 |
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| author | Yihan Ma Chongfu Zhao Jingjing Feng Junjie Gou Enci Kang Feng Guan Qiong Wu Xiang Li |
| author_facet | Yihan Ma Chongfu Zhao Jingjing Feng Junjie Gou Enci Kang Feng Guan Qiong Wu Xiang Li |
| author_sort | Yihan Ma |
| collection | DOAJ |
| description | Abstract Background The senescence of bone marrow mesenchymal stem cells (BMMSCs) is increasingly recognized as a critical factor contributing to the pathophysiology of age-related diseases. Recent studies suggest that small extracellular vesicles (sEVs) derived from the serum of elderly individuals may play a pivotal role in promoting BMMSC senescence. Glycoprotein non-metastatic melanoma protein B (GPNMB), a type I transmembrane glycoprotein, is upregulated during cellular senescence and can regulate stem cell ageing. However, the precise mechanisms by which GPNMB influences BMMSCs senescence remain poorly understood. Understanding this relationship could provide valuable insights into therapeutic strategies for enhancing BMMSCs function and mitigating age-related degeneration. Methods In this study, we conducted comprehensive in vitro experiments to elucidate the effects of sEVs isolated from the serum of elderly donors on the senescence of BMMSCs. We employed advanced proteomic analysis to quantify the expression levels of GPNMB in both BMMSCs and sEVs. Statistical methods were utilized to investigate the correlations between GPNMB expression, glycosylation modifications, and established senescence markers. Results Our findings demonstrate a robust positive correlation between the expression of GPNMB in BMMSCs and sEVs and the induction of cellular senescence. Notably, we observed that elevated levels of GPNMB, particularly those bearing bisecting N-acetylglucosamine (GlcNAc) modifications, significantly enhance the senescent phenotype of BMMSCs. Furthermore, we identified the bisecting GlcNAc modification at the Asn 249 residue of GPNMB as a critical determinant for its senescence-promoting function. Conclusions This study elucidates the substantial role of sEVs derived from mesenchymal stem cells in exacerbating BMMSC senescence through mechanisms that are critically dependent on the presence of bisecting GlcNAcylated GPNMB. These insights emphasize the necessity of targeting glycosylation modifications of GPNMB in the design of novel senolytic therapies aimed at mitigating cellular ageing and its associated pathologies. |
| format | Article |
| id | doaj-art-2729adaa20fa43d2bbd1cfd793648679 |
| institution | Kabale University |
| issn | 1757-6512 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj-art-2729adaa20fa43d2bbd1cfd7936486792025-01-26T12:18:03ZengBMCStem Cell Research & Therapy1757-65122025-01-0116111510.1186/s13287-025-04140-9MSC-sEVs exacerbate senescence by transferring bisecting GlcNAcylated GPNMBYihan Ma0Chongfu Zhao1Jingjing Feng2Junjie Gou3Enci Kang4Feng Guan5Qiong Wu6Xiang Li7Key Laboratory of Resource Biology and Biotechnology in Western China, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Ministry of Education, Northwest UniversityKey Laboratory of Resource Biology and Biotechnology in Western China, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Ministry of Education, Northwest UniversityKey Laboratory of Resource Biology and Biotechnology in Western China, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Ministry of Education, Northwest UniversityKey Laboratory of Resource Biology and Biotechnology in Western China, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Ministry of Education, Northwest UniversityXi’an Gaoxin No.1 High School International DivisionKey Laboratory of Resource Biology and Biotechnology in Western China, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Ministry of Education, Northwest UniversityThe First Affiliated Hospital of Northwest UniversityKey Laboratory of Resource Biology and Biotechnology in Western China, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Ministry of Education, Northwest UniversityAbstract Background The senescence of bone marrow mesenchymal stem cells (BMMSCs) is increasingly recognized as a critical factor contributing to the pathophysiology of age-related diseases. Recent studies suggest that small extracellular vesicles (sEVs) derived from the serum of elderly individuals may play a pivotal role in promoting BMMSC senescence. Glycoprotein non-metastatic melanoma protein B (GPNMB), a type I transmembrane glycoprotein, is upregulated during cellular senescence and can regulate stem cell ageing. However, the precise mechanisms by which GPNMB influences BMMSCs senescence remain poorly understood. Understanding this relationship could provide valuable insights into therapeutic strategies for enhancing BMMSCs function and mitigating age-related degeneration. Methods In this study, we conducted comprehensive in vitro experiments to elucidate the effects of sEVs isolated from the serum of elderly donors on the senescence of BMMSCs. We employed advanced proteomic analysis to quantify the expression levels of GPNMB in both BMMSCs and sEVs. Statistical methods were utilized to investigate the correlations between GPNMB expression, glycosylation modifications, and established senescence markers. Results Our findings demonstrate a robust positive correlation between the expression of GPNMB in BMMSCs and sEVs and the induction of cellular senescence. Notably, we observed that elevated levels of GPNMB, particularly those bearing bisecting N-acetylglucosamine (GlcNAc) modifications, significantly enhance the senescent phenotype of BMMSCs. Furthermore, we identified the bisecting GlcNAc modification at the Asn 249 residue of GPNMB as a critical determinant for its senescence-promoting function. Conclusions This study elucidates the substantial role of sEVs derived from mesenchymal stem cells in exacerbating BMMSC senescence through mechanisms that are critically dependent on the presence of bisecting GlcNAcylated GPNMB. These insights emphasize the necessity of targeting glycosylation modifications of GPNMB in the design of novel senolytic therapies aimed at mitigating cellular ageing and its associated pathologies.https://doi.org/10.1186/s13287-025-04140-9Bisecting GlcNAcGPNMBBone marrow mesenchymal stem cellsSmall extracellular vesiclesSenescence |
| spellingShingle | Yihan Ma Chongfu Zhao Jingjing Feng Junjie Gou Enci Kang Feng Guan Qiong Wu Xiang Li MSC-sEVs exacerbate senescence by transferring bisecting GlcNAcylated GPNMB Stem Cell Research & Therapy Bisecting GlcNAc GPNMB Bone marrow mesenchymal stem cells Small extracellular vesicles Senescence |
| title | MSC-sEVs exacerbate senescence by transferring bisecting GlcNAcylated GPNMB |
| title_full | MSC-sEVs exacerbate senescence by transferring bisecting GlcNAcylated GPNMB |
| title_fullStr | MSC-sEVs exacerbate senescence by transferring bisecting GlcNAcylated GPNMB |
| title_full_unstemmed | MSC-sEVs exacerbate senescence by transferring bisecting GlcNAcylated GPNMB |
| title_short | MSC-sEVs exacerbate senescence by transferring bisecting GlcNAcylated GPNMB |
| title_sort | msc sevs exacerbate senescence by transferring bisecting glcnacylated gpnmb |
| topic | Bisecting GlcNAc GPNMB Bone marrow mesenchymal stem cells Small extracellular vesicles Senescence |
| url | https://doi.org/10.1186/s13287-025-04140-9 |
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