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

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

10 Citaten (Scopus)

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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.

Originele taal-2	Engels
Pagina's (van-tot)	2417-2433.e7
Tijdschrift	Molecular Cell
Volume	83
Nummer van het tijdschrift	14
DOI's	https://doi.org/10.1016/j.molcel.2023.05.035
Status	Gepubliceerd - 20 jul. 2023

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10.1016/j.molcel.2023.05.035

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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

@article{96977cc478ce42beb40c65cfa3f43c00,

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 = "Animals, Mice, Aging, Hematopoiesis, Tumor Suppressor Protein p53/genetics, DNA Damage, Aldehydes/metabolism, Transcriptome, Single-Cell Gene Expression Analysis, Hematopoietic Stem Cells/cytology, Myeloid Cells/cytology, Humans, Leukemia, Myeloid, Acute/metabolism",

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}",

year = "2023",

month = jul,

day = "20",

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

language = "English",

volume = "83",

pages = "2417--2433.e7",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "14",

}

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, nr. 14, blz. 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 - Animals

KW - Mice

KW - Aging

KW - Hematopoiesis

KW - Tumor Suppressor Protein p53/genetics

KW - DNA Damage

KW - Aldehydes/metabolism

KW - Transcriptome

KW - Single-Cell Gene Expression Analysis

KW - Hematopoietic Stem Cells/cytology

KW - Myeloid Cells/cytology

KW - Humans

KW - Leukemia, Myeloid, Acute/metabolism

U2 - 10.1016/j.molcel.2023.05.035

DO - 10.1016/j.molcel.2023.05.035

M3 - Article

C2 - 37348497

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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