Amelioration of premature aging in Werner syndrome stem cells by targeting SHIP/AKT pathway
Abstract Background Pathogenic or null mutations in WRN helicase is a cause of premature aging disease Werner syndrome (WS). WRN is known to protect somatic cells including adult stem cells from premature senescence. Loss of WRN in mesenchymal stem cells (MSCs) not only drives the cells to premature...
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BMC
2025-01-01
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| Series: | Cell & Bioscience |
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| Online Access: | https://doi.org/10.1186/s13578-025-01355-4 |
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| author | Hei-Yin Tam Jiaxing Liu Tsz-Ching Yiu Adrian On-Wah Leung Chang Li Shen Gu Owen Rennert Boxian Huang Hoi-Hung Cheung |
| author_facet | Hei-Yin Tam Jiaxing Liu Tsz-Ching Yiu Adrian On-Wah Leung Chang Li Shen Gu Owen Rennert Boxian Huang Hoi-Hung Cheung |
| author_sort | Hei-Yin Tam |
| collection | DOAJ |
| description | Abstract Background Pathogenic or null mutations in WRN helicase is a cause of premature aging disease Werner syndrome (WS). WRN is known to protect somatic cells including adult stem cells from premature senescence. Loss of WRN in mesenchymal stem cells (MSCs) not only drives the cells to premature senescence but also significantly impairs the function of the stem cells in tissue repair or regeneration. Results In this study, we profiled the signaling pathways altered in WRN-deficient MSC and applied pharmacological method to activate the AKT signaling in these cells and examined their cellular phenotype related to aging. We found that the AKT signaling in WRN-deficient MSCs was significantly suppressed while the AKT upstream phosphatases (SHIP1/2) were upregulated. Knockdown or inhibition of SHIP1/2 could ameliorate premature senescence in WRN-deficient MSCs. Moreover, SHIP inhibition stimulated MSC proliferation and suppressed expression of pro-inflammatory cytokines IL-6 and IL-8. The stemness of WRN-deficient MSC was also improved upon pharmacological treatments with the inhibitors. Conclusions These results suggested that targeting the SHIP/AKT signaling pathway is beneficial to WRN-deficient stem cells and fibroblasts, which might be applied for improving the trophic function of MSC in, for instance, promoting angiogenesis. |
| format | Article |
| id | doaj-art-addc17dd55eb47f89745ff28dcf644e1 |
| institution | Kabale University |
| issn | 2045-3701 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj-art-addc17dd55eb47f89745ff28dcf644e12025-01-26T12:54:21ZengBMCCell & Bioscience2045-37012025-01-0115111410.1186/s13578-025-01355-4Amelioration of premature aging in Werner syndrome stem cells by targeting SHIP/AKT pathwayHei-Yin Tam0Jiaxing Liu1Tsz-Ching Yiu2Adrian On-Wah Leung3Chang Li4Shen Gu5Owen Rennert6Boxian Huang7Hoi-Hung Cheung8School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong KongSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong KongSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong KongSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong KongSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong KongSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong KongEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthState Key Laboratory of Reproductive Medicine, Nanjing Medical UniversitySchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong KongAbstract Background Pathogenic or null mutations in WRN helicase is a cause of premature aging disease Werner syndrome (WS). WRN is known to protect somatic cells including adult stem cells from premature senescence. Loss of WRN in mesenchymal stem cells (MSCs) not only drives the cells to premature senescence but also significantly impairs the function of the stem cells in tissue repair or regeneration. Results In this study, we profiled the signaling pathways altered in WRN-deficient MSC and applied pharmacological method to activate the AKT signaling in these cells and examined their cellular phenotype related to aging. We found that the AKT signaling in WRN-deficient MSCs was significantly suppressed while the AKT upstream phosphatases (SHIP1/2) were upregulated. Knockdown or inhibition of SHIP1/2 could ameliorate premature senescence in WRN-deficient MSCs. Moreover, SHIP inhibition stimulated MSC proliferation and suppressed expression of pro-inflammatory cytokines IL-6 and IL-8. The stemness of WRN-deficient MSC was also improved upon pharmacological treatments with the inhibitors. Conclusions These results suggested that targeting the SHIP/AKT signaling pathway is beneficial to WRN-deficient stem cells and fibroblasts, which might be applied for improving the trophic function of MSC in, for instance, promoting angiogenesis.https://doi.org/10.1186/s13578-025-01355-4Werner syndromeAKT signalingSHIPSenescenceWRNMesenchymal stem cell |
| spellingShingle | Hei-Yin Tam Jiaxing Liu Tsz-Ching Yiu Adrian On-Wah Leung Chang Li Shen Gu Owen Rennert Boxian Huang Hoi-Hung Cheung Amelioration of premature aging in Werner syndrome stem cells by targeting SHIP/AKT pathway Cell & Bioscience Werner syndrome AKT signaling SHIP Senescence WRN Mesenchymal stem cell |
| title | Amelioration of premature aging in Werner syndrome stem cells by targeting SHIP/AKT pathway |
| title_full | Amelioration of premature aging in Werner syndrome stem cells by targeting SHIP/AKT pathway |
| title_fullStr | Amelioration of premature aging in Werner syndrome stem cells by targeting SHIP/AKT pathway |
| title_full_unstemmed | Amelioration of premature aging in Werner syndrome stem cells by targeting SHIP/AKT pathway |
| title_short | Amelioration of premature aging in Werner syndrome stem cells by targeting SHIP/AKT pathway |
| title_sort | amelioration of premature aging in werner syndrome stem cells by targeting ship akt pathway |
| topic | Werner syndrome AKT signaling SHIP Senescence WRN Mesenchymal stem cell |
| url | https://doi.org/10.1186/s13578-025-01355-4 |
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