Mesenchymal stem cells reverse thymus aging by reprogramming the DNA methylation of thymic epithelial cells
Background: A decrease in the number and activity of thymic epithelial cells (TECs) is an important factor in thymic degeneration. Mesenchymal stem cells (MSCs) treating thymic ageing is a promising strategy, but the DNA methylation modification mechanism in TECs remains unclear. Methods: Aged rhesu...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-12-01
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| Series: | Regenerative Therapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352320424000397 |
| _version_ | 1827246288252436480 |
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| author | Zailing Yang Chuan Tian Zhixu He Xiangqing Zhu Jie He Hang Pan Ye Li Guangping Ruan XiJun Wu Xinghua Pan |
| author_facet | Zailing Yang Chuan Tian Zhixu He Xiangqing Zhu Jie He Hang Pan Ye Li Guangping Ruan XiJun Wu Xinghua Pan |
| author_sort | Zailing Yang |
| collection | DOAJ |
| description | Background: A decrease in the number and activity of thymic epithelial cells (TECs) is an important factor in thymic degeneration. Mesenchymal stem cells (MSCs) treating thymic ageing is a promising strategy, but the DNA methylation modification mechanism in TECs remains unclear. Methods: Aged rhesus monkeys were treated with MSCs to establish a thymic senescence model, and hematoxylin-eosin (HE) staining, immunofluorescence staining, and ELISA were performed to observe the structure and function of the thymus. TEC aging model and MSCs co-culture system were established to detect DNA methylation modification and transcriptomic changes, correlation analysis between transcription factor methylation and mRNA expression, and q-PCR, immunofluorescence staining, and Western blot were used to identified key genes. Results: MSCs improved the structure and function of thymus in elderly macaque monkeys; reduced the expression levels of β-Gal, P16, and P21; and increased the activity of aging TECs. There were 501 genes with increased methylation in the promoter region in the treated group compared with the untreated group, among which 23 genes were involved in the negative regulation of cell growth, proliferation and apoptosis, while 591 genes had decreased methylation, among which 37 genes were associated with promoting cell growth and proliferation and inhibiting apoptosis. Furthermore, 66 genes showed a negative correlation between promoter methylation levels and gene transcription; specifically, PDE5A, DUOX2, LAMP1 and SVIL were downregulated with increased methylation, inhibiting growth and development, while POLR3G, PGF, CHTF18, KRT17, FOXJ1, NGF, DYRK3, LRP8, CDT1, PRELID1, F2R, KNTC1 and TRIM3 were upregulated with decreased methylation, promoting cell growth. Conclusion: MSCs improve the structure and function of aged thymus, which involves the regulation of DNA methylation profiles and a decrease in the methylation level of the transcription factor NGF to specifically upregulate KRT17 and FOXJ1 to promote the proliferation of TECs. |
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| format | Article |
| id | doaj.art-7ee33dd2d9ce4ab89356c16d854c398e |
| institution | Directory Open Access Journal |
| issn | 2352-3204 |
| language | English |
| last_indexed | 2025-03-21T22:57:34Z |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Regenerative Therapy |
| spelling | doaj.art-7ee33dd2d9ce4ab89356c16d854c398e2024-05-23T04:56:14ZengElsevierRegenerative Therapy2352-32042024-12-0127126169Mesenchymal stem cells reverse thymus aging by reprogramming the DNA methylation of thymic epithelial cellsZailing Yang0Chuan Tian1Zhixu He2Xiangqing Zhu3Jie He4Hang Pan5Ye Li6Guangping Ruan7XiJun Wu8Xinghua Pan9The Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, China; The Second People's Hospital of Guiyang, Medical Laboratory, Guiyang 550023, Guizhou Province, ChinaThe Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, ChinaDepartment of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, ChinaThe Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, ChinaThe Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, ChinaThe Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, ChinaThe Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, ChinaThe Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, ChinaThe Second People's Hospital of Guiyang, Medical Laboratory, Guiyang 550023, Guizhou Province, China; Corresponding author.The Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, China; Corresponding author.Background: A decrease in the number and activity of thymic epithelial cells (TECs) is an important factor in thymic degeneration. Mesenchymal stem cells (MSCs) treating thymic ageing is a promising strategy, but the DNA methylation modification mechanism in TECs remains unclear. Methods: Aged rhesus monkeys were treated with MSCs to establish a thymic senescence model, and hematoxylin-eosin (HE) staining, immunofluorescence staining, and ELISA were performed to observe the structure and function of the thymus. TEC aging model and MSCs co-culture system were established to detect DNA methylation modification and transcriptomic changes, correlation analysis between transcription factor methylation and mRNA expression, and q-PCR, immunofluorescence staining, and Western blot were used to identified key genes. Results: MSCs improved the structure and function of thymus in elderly macaque monkeys; reduced the expression levels of β-Gal, P16, and P21; and increased the activity of aging TECs. There were 501 genes with increased methylation in the promoter region in the treated group compared with the untreated group, among which 23 genes were involved in the negative regulation of cell growth, proliferation and apoptosis, while 591 genes had decreased methylation, among which 37 genes were associated with promoting cell growth and proliferation and inhibiting apoptosis. Furthermore, 66 genes showed a negative correlation between promoter methylation levels and gene transcription; specifically, PDE5A, DUOX2, LAMP1 and SVIL were downregulated with increased methylation, inhibiting growth and development, while POLR3G, PGF, CHTF18, KRT17, FOXJ1, NGF, DYRK3, LRP8, CDT1, PRELID1, F2R, KNTC1 and TRIM3 were upregulated with decreased methylation, promoting cell growth. Conclusion: MSCs improve the structure and function of aged thymus, which involves the regulation of DNA methylation profiles and a decrease in the methylation level of the transcription factor NGF to specifically upregulate KRT17 and FOXJ1 to promote the proliferation of TECs.http://www.sciencedirect.com/science/article/pii/S2352320424000397Thymus agingMSCsTECsDNA methylation |
| spellingShingle | Zailing Yang Chuan Tian Zhixu He Xiangqing Zhu Jie He Hang Pan Ye Li Guangping Ruan XiJun Wu Xinghua Pan Mesenchymal stem cells reverse thymus aging by reprogramming the DNA methylation of thymic epithelial cells Regenerative Therapy Thymus aging MSCs TECs DNA methylation |
| title | Mesenchymal stem cells reverse thymus aging by reprogramming the DNA methylation of thymic epithelial cells |
| title_full | Mesenchymal stem cells reverse thymus aging by reprogramming the DNA methylation of thymic epithelial cells |
| title_fullStr | Mesenchymal stem cells reverse thymus aging by reprogramming the DNA methylation of thymic epithelial cells |
| title_full_unstemmed | Mesenchymal stem cells reverse thymus aging by reprogramming the DNA methylation of thymic epithelial cells |
| title_short | Mesenchymal stem cells reverse thymus aging by reprogramming the DNA methylation of thymic epithelial cells |
| title_sort | mesenchymal stem cells reverse thymus aging by reprogramming the dna methylation of thymic epithelial cells |
| topic | Thymus aging MSCs TECs DNA methylation |
| url | http://www.sciencedirect.com/science/article/pii/S2352320424000397 |
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