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通过靶向SHIP/AKT通路改善沃纳综合征干细胞的早衰

Amelioration of premature aging in Werner syndrome stem cells by targeting SHIP/AKT pathway.

作者信息

Tam Hei-Yin, Liu Jiaxing, Yiu Tsz-Ching, Leung Adrian On-Wah, Li Chang, Gu Shen, Rennert Owen, Huang Boxian, Cheung Hoi-Hung

机构信息

School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong S.A.R., China.

Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences, Hong Kong, China.

出版信息

Cell Biosci. 2025 Jan 25;15(1):10. doi: 10.1186/s13578-025-01355-4.

DOI:10.1186/s13578-025-01355-4
PMID:39863890
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11765919/
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.

摘要

背景

WRN解旋酶的致病或无效突变是早衰疾病沃纳综合征（WS）的病因。已知WRN可保护包括成体干细胞在内的体细胞免于过早衰老。间充质干细胞（MSC）中WRN的缺失不仅会促使细胞过早衰老，还会显著损害干细胞在组织修复或再生中的功能。

结果

在本研究中，我们分析了WRN缺陷型MSC中改变的信号通路，并应用药理学方法激活这些细胞中的AKT信号通路，并检测它们与衰老相关的细胞表型。我们发现WRN缺陷型MSC中的AKT信号通路被显著抑制，而AKT上游磷酸酶（SHIP1/2）上调。敲低或抑制SHIP1/2可改善WRN缺陷型MSC的过早衰老。此外，SHIP抑制可刺激MSC增殖并抑制促炎细胞因子IL-6和IL-8的表达。用抑制剂进行药理学处理后，WRN缺陷型MSC的干性也得到改善。

结论

这些结果表明，靶向SHIP/AKT信号通路对WRN缺陷型干细胞和成纤维细胞有益，这可能用于改善MSC的营养功能，例如促进血管生成。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/4b258cc20595/13578_2025_1355_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/94eff5e2f730/13578_2025_1355_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/0d7ba3b90a14/13578_2025_1355_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/10c062990e80/13578_2025_1355_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/9d701c684aec/13578_2025_1355_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/83668a656678/13578_2025_1355_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/bd00677574f8/13578_2025_1355_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/39332e1b7c66/13578_2025_1355_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/4b258cc20595/13578_2025_1355_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/94eff5e2f730/13578_2025_1355_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/0d7ba3b90a14/13578_2025_1355_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/10c062990e80/13578_2025_1355_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/9d701c684aec/13578_2025_1355_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/83668a656678/13578_2025_1355_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/bd00677574f8/13578_2025_1355_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/39332e1b7c66/13578_2025_1355_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82e/11765919/4b258cc20595/13578_2025_1355_Fig8_HTML.jpg

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