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Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1‐expanded human cord blood CD34 (+) cells via inhibition of senescence
The stemness of ex vivo expanded hematopoietic stem cells (HSCs) is usually compromised by current methods. To explore the failure mechanism of stemness maintenance of human HSCs, which were expanded from human umbilical cord blood (hUCB) CD34(+) cells, by differentiation inhibitor Stem Regenin 1 (S...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695631/ https://www.ncbi.nlm.nih.gov/pubmed/32602209 http://dx.doi.org/10.1002/sctm.20-0129 |
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author | Li, Xiaoyi Ma, Xiao Chen, Ying Peng, Danyue Wang, Huifang Chen, Suhua Xiao, Yin Li, Lei Zhou, Hao Cheng, Fanjun Gao, Yingdai Chang, Jiwei Cheng, Tao Liu, Lingbo |
author_facet | Li, Xiaoyi Ma, Xiao Chen, Ying Peng, Danyue Wang, Huifang Chen, Suhua Xiao, Yin Li, Lei Zhou, Hao Cheng, Fanjun Gao, Yingdai Chang, Jiwei Cheng, Tao Liu, Lingbo |
author_sort | Li, Xiaoyi |
collection | PubMed |
description | The stemness of ex vivo expanded hematopoietic stem cells (HSCs) is usually compromised by current methods. To explore the failure mechanism of stemness maintenance of human HSCs, which were expanded from human umbilical cord blood (hUCB) CD34(+) cells, by differentiation inhibitor Stem Regenin 1 (SR1), an antagonist of aryl hydrocarbon receptor, we investigated the activity of p38 mitogen‐activated protein kinase α (p38 MAPKα, p38α) and mammalian target of rapamycin complex 1 (mTORC1), and their effect on SR1‐expanded hUCB CD34(+) cells. Our results showed that cellular senescence occurred in the SR1‐expanded hUCB CD34(+) cells in which p38α and mTORC1 were successively activated. Furthermore, their coinhibition resulted in a further decrease in hUCB CD34(+) cell senescence without an effect on apoptosis, promoted the maintenance of expanded phenotypic HSCs without differentiation inhibition, increased the hematopoietic reconstitution ability of multiple lineages, and potentiated the long‐term self‐renewal capability of HSCs from SR1‐expanded hUCB CD34(+) cells in NOD/Shi‐scid/IL‐2Rγ(null) mice. Our mechanistic study revealed that senescence inhibition by our strategy was mainly attributed to downregulation of the splicesome, proteasome formation, and pyrimidine metabolism signaling pathways. These results suggest that coinhibition of activated p38α and mTORC1 potentiates stemness maintenance of HSCs from SR1‐expanded hUCB CD34(+) cells via senescence inhibition. Thus, we established a new strategy to maintain the stemness of ex vivo differentiation inhibitor‐expanded human HSCs via coinhibition of multiple independent senescence initiating signal pathways. This senescence inhibition‐induced stemness maintenance of ex vivo expanded HSCs could also have an important role in other HSC expansion systems. |
format | Online Article Text |
id | pubmed-7695631 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley & Sons, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-76956312020-12-10 Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1‐expanded human cord blood CD34 (+) cells via inhibition of senescence Li, Xiaoyi Ma, Xiao Chen, Ying Peng, Danyue Wang, Huifang Chen, Suhua Xiao, Yin Li, Lei Zhou, Hao Cheng, Fanjun Gao, Yingdai Chang, Jiwei Cheng, Tao Liu, Lingbo Stem Cells Transl Med Tissue Engineering and Regenerative Medicine The stemness of ex vivo expanded hematopoietic stem cells (HSCs) is usually compromised by current methods. To explore the failure mechanism of stemness maintenance of human HSCs, which were expanded from human umbilical cord blood (hUCB) CD34(+) cells, by differentiation inhibitor Stem Regenin 1 (SR1), an antagonist of aryl hydrocarbon receptor, we investigated the activity of p38 mitogen‐activated protein kinase α (p38 MAPKα, p38α) and mammalian target of rapamycin complex 1 (mTORC1), and their effect on SR1‐expanded hUCB CD34(+) cells. Our results showed that cellular senescence occurred in the SR1‐expanded hUCB CD34(+) cells in which p38α and mTORC1 were successively activated. Furthermore, their coinhibition resulted in a further decrease in hUCB CD34(+) cell senescence without an effect on apoptosis, promoted the maintenance of expanded phenotypic HSCs without differentiation inhibition, increased the hematopoietic reconstitution ability of multiple lineages, and potentiated the long‐term self‐renewal capability of HSCs from SR1‐expanded hUCB CD34(+) cells in NOD/Shi‐scid/IL‐2Rγ(null) mice. Our mechanistic study revealed that senescence inhibition by our strategy was mainly attributed to downregulation of the splicesome, proteasome formation, and pyrimidine metabolism signaling pathways. These results suggest that coinhibition of activated p38α and mTORC1 potentiates stemness maintenance of HSCs from SR1‐expanded hUCB CD34(+) cells via senescence inhibition. Thus, we established a new strategy to maintain the stemness of ex vivo differentiation inhibitor‐expanded human HSCs via coinhibition of multiple independent senescence initiating signal pathways. This senescence inhibition‐induced stemness maintenance of ex vivo expanded HSCs could also have an important role in other HSC expansion systems. John Wiley & Sons, Inc. 2020-06-29 /pmc/articles/PMC7695631/ /pubmed/32602209 http://dx.doi.org/10.1002/sctm.20-0129 Text en © 2020 The Authors. stem cells translational medicine published by Wiley Periodicals LLC on behalf of AlphaMed Press This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Tissue Engineering and Regenerative Medicine Li, Xiaoyi Ma, Xiao Chen, Ying Peng, Danyue Wang, Huifang Chen, Suhua Xiao, Yin Li, Lei Zhou, Hao Cheng, Fanjun Gao, Yingdai Chang, Jiwei Cheng, Tao Liu, Lingbo Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1‐expanded human cord blood CD34 (+) cells via inhibition of senescence |
title | Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1‐expanded human cord blood CD34
(+) cells via inhibition of senescence |
title_full | Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1‐expanded human cord blood CD34
(+) cells via inhibition of senescence |
title_fullStr | Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1‐expanded human cord blood CD34
(+) cells via inhibition of senescence |
title_full_unstemmed | Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1‐expanded human cord blood CD34
(+) cells via inhibition of senescence |
title_short | Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1‐expanded human cord blood CD34
(+) cells via inhibition of senescence |
title_sort | coinhibition of activated p38 mapkα and mtorc1 potentiates stemness maintenance of hscs from sr1‐expanded human cord blood cd34
(+) cells via inhibition of senescence |
topic | Tissue Engineering and Regenerative Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695631/ https://www.ncbi.nlm.nih.gov/pubmed/32602209 http://dx.doi.org/10.1002/sctm.20-0129 |
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