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Silencing circSERPINE2 restrains mesenchymal stem cell senescence via the YBX3/PCNA/p21 axis
Increasing evidence indicates that circular RNAs (circRNAs) accumulate in aging tissues and nonproliferating cells due to their high stability. However, whether upregulation of circRNA expression mediates stem cell senescence and whether circRNAs can be targeted to alleviate aging-related disorders...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10575817/ https://www.ncbi.nlm.nih.gov/pubmed/37831180 http://dx.doi.org/10.1007/s00018-023-04975-6 |
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author | Chen, Fenglei Wang, Shan Zeng, Chenying Tang, Su’an Gu, Huimin Wang, Ziming Li, Jinteng Feng, Pei Zhang, Yunhui Wang, Peng Wu, Yanfeng Shen, Huiyong |
author_facet | Chen, Fenglei Wang, Shan Zeng, Chenying Tang, Su’an Gu, Huimin Wang, Ziming Li, Jinteng Feng, Pei Zhang, Yunhui Wang, Peng Wu, Yanfeng Shen, Huiyong |
author_sort | Chen, Fenglei |
collection | PubMed |
description | Increasing evidence indicates that circular RNAs (circRNAs) accumulate in aging tissues and nonproliferating cells due to their high stability. However, whether upregulation of circRNA expression mediates stem cell senescence and whether circRNAs can be targeted to alleviate aging-related disorders remain unclear. Here, RNA sequencing analysis of differentially expressed circRNAs in long-term-cultured mesenchymal stem cells (MSCs) revealed that circSERPINE2 expression was significantly increased in late passages. CircSERPINE2 small interfering RNA delayed MSC senescence and rejuvenated MSCs, while circSERPINE2 overexpression had the opposite effect. RNA pulldown followed by mass spectrometry revealed an interaction between circSERPINE2 and YBX3. CircSERPINE2 increased the affinity of YBX3 for ZO-1 through the CCAUC motif, resulting in the sequestration of YBX3 in the cytoplasm, inhibiting the association of YBX3 with the PCNA promoter and eventually affecting p21 ubiquitin-mediated degradation. In addition, our results demonstrated that senescence-related downregulation of EIF4A3 gave rise to circSERPINE2. In vivo, intra-articular injection of si-circSerpine2 restrained native joint-resident MSC senescence and cartilage degeneration in mice with aging-related osteoarthritis. Taken together, our findings provide strong evidence for a regulatory role for the circSERPINE2/YBX3/PCNA/p21 axis in MSC senescence and the therapeutic potential of si-circSERPINE2 in alleviating aging-associated syndromes, such as osteoarthritis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-023-04975-6. |
format | Online Article Text |
id | pubmed-10575817 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-105758172023-10-15 Silencing circSERPINE2 restrains mesenchymal stem cell senescence via the YBX3/PCNA/p21 axis Chen, Fenglei Wang, Shan Zeng, Chenying Tang, Su’an Gu, Huimin Wang, Ziming Li, Jinteng Feng, Pei Zhang, Yunhui Wang, Peng Wu, Yanfeng Shen, Huiyong Cell Mol Life Sci Original Article Increasing evidence indicates that circular RNAs (circRNAs) accumulate in aging tissues and nonproliferating cells due to their high stability. However, whether upregulation of circRNA expression mediates stem cell senescence and whether circRNAs can be targeted to alleviate aging-related disorders remain unclear. Here, RNA sequencing analysis of differentially expressed circRNAs in long-term-cultured mesenchymal stem cells (MSCs) revealed that circSERPINE2 expression was significantly increased in late passages. CircSERPINE2 small interfering RNA delayed MSC senescence and rejuvenated MSCs, while circSERPINE2 overexpression had the opposite effect. RNA pulldown followed by mass spectrometry revealed an interaction between circSERPINE2 and YBX3. CircSERPINE2 increased the affinity of YBX3 for ZO-1 through the CCAUC motif, resulting in the sequestration of YBX3 in the cytoplasm, inhibiting the association of YBX3 with the PCNA promoter and eventually affecting p21 ubiquitin-mediated degradation. In addition, our results demonstrated that senescence-related downregulation of EIF4A3 gave rise to circSERPINE2. In vivo, intra-articular injection of si-circSerpine2 restrained native joint-resident MSC senescence and cartilage degeneration in mice with aging-related osteoarthritis. Taken together, our findings provide strong evidence for a regulatory role for the circSERPINE2/YBX3/PCNA/p21 axis in MSC senescence and the therapeutic potential of si-circSERPINE2 in alleviating aging-associated syndromes, such as osteoarthritis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-023-04975-6. Springer International Publishing 2023-10-13 2023 /pmc/articles/PMC10575817/ /pubmed/37831180 http://dx.doi.org/10.1007/s00018-023-04975-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Chen, Fenglei Wang, Shan Zeng, Chenying Tang, Su’an Gu, Huimin Wang, Ziming Li, Jinteng Feng, Pei Zhang, Yunhui Wang, Peng Wu, Yanfeng Shen, Huiyong Silencing circSERPINE2 restrains mesenchymal stem cell senescence via the YBX3/PCNA/p21 axis |
title | Silencing circSERPINE2 restrains mesenchymal stem cell senescence via the YBX3/PCNA/p21 axis |
title_full | Silencing circSERPINE2 restrains mesenchymal stem cell senescence via the YBX3/PCNA/p21 axis |
title_fullStr | Silencing circSERPINE2 restrains mesenchymal stem cell senescence via the YBX3/PCNA/p21 axis |
title_full_unstemmed | Silencing circSERPINE2 restrains mesenchymal stem cell senescence via the YBX3/PCNA/p21 axis |
title_short | Silencing circSERPINE2 restrains mesenchymal stem cell senescence via the YBX3/PCNA/p21 axis |
title_sort | silencing circserpine2 restrains mesenchymal stem cell senescence via the ybx3/pcna/p21 axis |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10575817/ https://www.ncbi.nlm.nih.gov/pubmed/37831180 http://dx.doi.org/10.1007/s00018-023-04975-6 |
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