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

Meng Wang; Laura T.L. Brandt; Xiaonan Wang; Holly Russell; Emily Mitchell; Ashley N. Kamimae-Lanning; Jill M. Brown; Felix A. Dingler; Juan I. Garaycoechea; Tomoya Isobe; Sarah J. Kinston; Muxin Gu; George S. Vassiliou; Nicola K. Wilson; Berthold Göttgens; Ketan J. Patel

doi:10.1016/j.molcel.2023.05.035

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

Meng Wang^*, Laura T.L. Brandt, Xiaonan Wang, Holly Russell, Emily Mitchell, Ashley N. Kamimae-Lanning, Jill M. Brown, Felix A. Dingler, Juan I. Garaycoechea, Tomoya Isobe, Sarah J. Kinston, Muxin Gu, George S. Vassiliou, Nicola K. Wilson, Berthold Göttgens, Ketan J. Patel^*

^*Corresponding author for this work

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Abstract

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.

Original language	English
Pages (from-to)	2417-2433.e7
Journal	Molecular Cell
Volume	83
Issue number	14
DOIs	https://doi.org/10.1016/j.molcel.2023.05.035
Publication status	Published - 20 Jul 2023

Keywords

aging
aldehydes
DNA damage
DNA-damage response
hematopoiesis
myeloid bias
p53

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10.1016/j.molcel.2023.05.035Licence: CC BY

1-s2.0-S1097276523004197-mainFinal published version, 7.01 MBLicence: CC BY

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Wang, M., Brandt, L. T. L., Wang, X., Russell, H., Mitchell, E., Kamimae-Lanning, A. N., Brown, J. M., Dingler, F. A., Garaycoechea, J. I., Isobe, T., Kinston, S. J., Gu, M., Vassiliou, G. S., Wilson, N. K., Göttgens, B., & Patel, K. J. (2023). Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner. Molecular Cell, 83(14), 2417-2433.e7. https://doi.org/10.1016/j.molcel.2023.05.035

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title = "Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner",

abstract = "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.",

keywords = "aging, aldehydes, DNA damage, DNA-damage response, hematopoiesis, myeloid bias, p53",

author = "Meng Wang and Brandt, {Laura T.L.} and Xiaonan Wang and Holly Russell and Emily Mitchell and Kamimae-Lanning, {Ashley N.} and Brown, {Jill M.} and Dingler, {Felix A.} and Garaycoechea, {Juan I.} and Tomoya Isobe and Kinston, {Sarah J.} and Muxin Gu and Vassiliou, {George S.} and Wilson, {Nicola K.} and Berthold G{\"o}ttgens and Patel, {Ketan J.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = jul,

day = "20",

doi = "10.1016/j.molcel.2023.05.035",

language = "English",

volume = "83",

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Wang, M, Brandt, LTL, Wang, X, Russell, H, Mitchell, E, Kamimae-Lanning, AN, Brown, JM, Dingler, FA, Garaycoechea, JI, Isobe, T, Kinston, SJ, Gu, M, Vassiliou, GS, Wilson, NK, Göttgens, B & Patel, KJ 2023, 'Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner', Molecular Cell, vol. 83, no. 14, pp. 2417-2433.e7. https://doi.org/10.1016/j.molcel.2023.05.035

TY - JOUR

T1 - Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner

AU - Wang, Meng

AU - Brandt, Laura T.L.

AU - Wang, Xiaonan

AU - Russell, Holly

AU - Mitchell, Emily

AU - Kamimae-Lanning, Ashley N.

AU - Brown, Jill M.

AU - Dingler, Felix A.

AU - Garaycoechea, Juan I.

AU - Isobe, Tomoya

AU - Kinston, Sarah J.

AU - Gu, Muxin

AU - Vassiliou, George S.

AU - Wilson, Nicola K.

AU - Göttgens, Berthold

AU - Patel, Ketan J.

PY - 2023/7/20

Y1 - 2023/7/20

N2 - 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.

AB - 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.

KW - aging

KW - aldehydes

KW - DNA damage

KW - DNA-damage response

KW - hematopoiesis

KW - myeloid bias

KW - p53

UR - http://www.scopus.com/inward/record.url?scp=85165405052&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2023.05.035

DO - 10.1016/j.molcel.2023.05.035

M3 - Article

C2 - 37348497

AN - SCOPUS:85165405052

SN - 1097-2765

VL - 83

SP - 2417-2433.e7

JO - Molecular Cell

JF - Molecular Cell

IS - 14

ER -

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

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