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

Mol Cell. 2023 Jul 20;83(14):2417-2433.e7. doi: 10.1016/j.molcel.2023.05.035. Epub 2023 Jun 21.

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: DNA damage; DNA-damage response; aging; aldehydes; hematopoiesis; myeloid bias; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Tumor Suppressor Protein p53
  • Aldehydes
  • ALDH2 protein, mouse
  • Fancd2 protein, mouse