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

Published version
Peer-reviewed

Repository DOI


Type

Article

Change log

Authors

Wang, Meng 
Brandt, Laura TL 
Wang, Xiaonan 
Russell, Holly 
Mitchell, Emily 

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.

Description

Keywords

DNA damage, DNA-damage response, aging, aldehydes, hematopoiesis, myeloid bias, p53, Animals, Mice, Aging, Hematopoiesis, Tumor Suppressor Protein p53, DNA Damage, Aldehydes, Transcriptome, Single-Cell Gene Expression Analysis, Hematopoietic Stem Cells, Myeloid Cells, Humans, Leukemia, Myeloid, Acute

Journal Title

Mol Cell

Conference Name

Journal ISSN

1097-2765
1097-4164

Volume Title

83

Publisher

Elsevier BV
Sponsorship
Cancer Research UK (21762)
Wellcome Trust (206328/Z/17/Z)
Wellcome Trust (203151/Z/16/Z)
Bloodwise (18002)
Medical Research Council (MR/S036113/1)
Medical Research Council (MC_PC_17230)
Wellcome Trust (203151/A/16/Z)