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 de

SUBMITTER: Wang M 

PROVIDER: S-EPMC7614878 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature