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Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner

Aged hematopoietic stem cells (HSCs) display diminished self-renewal and a myeloid differentiation bias. However, the drivers and mechanisms that underpin this fundamental switch are not understood. HSCs produce genotoxic formaldehyde that requires protection by the detoxification enzymes ALDH2 and...

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Autores principales: Wang, Meng, Brandt, Laura T.L., Wang, Xiaonan, Russell, Holly, Mitchell, Emily, Kamimae-Lanning, Ashley N., Brown, Jill M., Dingler, Felix A., Garaycoechea, Juan I., Isobe, Tomoya, Kinston, Sarah J., Gu, Muxin, Vassiliou, George S., Wilson, Nicola K., Göttgens, Berthold, Patel, Ketan J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7614878/
https://www.ncbi.nlm.nih.gov/pubmed/37348497
http://dx.doi.org/10.1016/j.molcel.2023.05.035
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author Wang, Meng
Brandt, Laura T.L.
Wang, Xiaonan
Russell, Holly
Mitchell, Emily
Kamimae-Lanning, Ashley N.
Brown, Jill M.
Dingler, Felix A.
Garaycoechea, Juan I.
Isobe, Tomoya
Kinston, Sarah J.
Gu, Muxin
Vassiliou, George S.
Wilson, Nicola K.
Göttgens, Berthold
Patel, Ketan J.
author_facet Wang, Meng
Brandt, Laura T.L.
Wang, Xiaonan
Russell, Holly
Mitchell, Emily
Kamimae-Lanning, Ashley N.
Brown, Jill M.
Dingler, Felix A.
Garaycoechea, Juan I.
Isobe, Tomoya
Kinston, Sarah J.
Gu, Muxin
Vassiliou, George S.
Wilson, Nicola K.
Göttgens, Berthold
Patel, Ketan J.
author_sort Wang, Meng
collection PubMed
description Aged hematopoietic stem cells (HSCs) display diminished self-renewal and a myeloid differentiation bias. However, the drivers and mechanisms that underpin this fundamental switch are not understood. HSCs produce genotoxic formaldehyde that requires protection by the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. We find that the HSCs in young Aldh2(−/−) Fancd2 (−/−) mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition, and myeloid-biased differentiation quantified by single HSC transplantation. In addition, the p53 response is vigorously activated in Aldh2 (−/−) Fancd2 (−/−) HSCs, while p53 deletion rescued this aged HSC phenotype. To further define the origins of the myeloid differentiation bias, we use a GFP genetic reporter to find a striking enrichment of Vwf+ myeloid and megakaryocyte-lineage-biased HSCs. These results indicate that metabolism-derived formaldehyde-DNA damage stimulates the p53 response in HSCs to drive accelerated aging.
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spelling pubmed-76148782023-08-04 Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner Wang, Meng Brandt, Laura T.L. Wang, Xiaonan Russell, Holly Mitchell, Emily Kamimae-Lanning, Ashley N. Brown, Jill M. Dingler, Felix A. Garaycoechea, Juan I. Isobe, Tomoya Kinston, Sarah J. Gu, Muxin Vassiliou, George S. Wilson, Nicola K. Göttgens, Berthold Patel, Ketan J. Mol Cell Article Aged hematopoietic stem cells (HSCs) display diminished self-renewal and a myeloid differentiation bias. However, the drivers and mechanisms that underpin this fundamental switch are not understood. HSCs produce genotoxic formaldehyde that requires protection by the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. We find that the HSCs in young Aldh2(−/−) Fancd2 (−/−) mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition, and myeloid-biased differentiation quantified by single HSC transplantation. In addition, the p53 response is vigorously activated in Aldh2 (−/−) Fancd2 (−/−) HSCs, while p53 deletion rescued this aged HSC phenotype. To further define the origins of the myeloid differentiation bias, we use a GFP genetic reporter to find a striking enrichment of Vwf+ myeloid and megakaryocyte-lineage-biased HSCs. These results indicate that metabolism-derived formaldehyde-DNA damage stimulates the p53 response in HSCs to drive accelerated aging. 2023-07-20 2023-06-21 /pmc/articles/PMC7614878/ /pubmed/37348497 http://dx.doi.org/10.1016/j.molcel.2023.05.035 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a BY 4.0 (https://creativecommons.org/licenses/by/4.0/) International license.
spellingShingle Article
Wang, Meng
Brandt, Laura T.L.
Wang, Xiaonan
Russell, Holly
Mitchell, Emily
Kamimae-Lanning, Ashley N.
Brown, Jill M.
Dingler, Felix A.
Garaycoechea, Juan I.
Isobe, Tomoya
Kinston, Sarah J.
Gu, Muxin
Vassiliou, George S.
Wilson, Nicola K.
Göttgens, Berthold
Patel, Ketan J.
Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner
title Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner
title_full Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner
title_fullStr Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner
title_full_unstemmed Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner
title_short Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner
title_sort genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7614878/
https://www.ncbi.nlm.nih.gov/pubmed/37348497
http://dx.doi.org/10.1016/j.molcel.2023.05.035
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