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| Status |
Public on May 24, 2023 |
| Title |
Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Aged hematopoietic stem cells (HSC) display diminished self-renewal and a myeloid differentiation bias. However, the physiological drivers and molecular processes that underpin this fundamental switch are not understood. HSCs produce formaldehyde and are protected from this metabolite by two tiers of protection: the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. Using single cell RNA sequencing, we find that the HSC and progenitor cells 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 progenitors. In addition, the p53 response is vigorously activated in Aldh2-/- Fancd2-/- HSCs, whilst p53 deletion rescued this aged transcriptomic signature and telomere attrition. Transplantation of single Aldh2-/- Fancd2-/- HSCs also reveals a predominantly myeloid output, which is reversed upon p53 deletion. To further define the origins of the myeloid differentiation bias, a GFP genetic reporter which detects Vwf+ myeloid primed HSCs was crossed into Aldh2-/- Fancd2-/- mice, revealing a striking enrichment
of these lineage-biased Vwf+ HSCs. These results indicate that metabolism derived formaldehyde causes endogenous DNA damage which stimulates the p53 response in HSCs, which then accelerates their aging, resulting in a myeloid lineage biased output.
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| Overall design |
Lin-Sca1+cKit+ cells from WT, Aldh2 knock-outs, Fancd2 knock-outs, p53 knock-outs, Aldh2 & Fancd2 double knock-outs, Aldh2 & Fancd2 & p53 triple knock-outs
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| Web link |
https://linkinghub.elsevier.com/retrieve/pii/S1097-2765(23)00419-7
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| Contributor(s) |
Wang M, Brandt LT, Wang X, Russel 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 |
| Citation(s) |
37348497 |
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| Submission date |
Jul 25, 2022 |
| Last update date |
Sep 11, 2023 |
| Contact name |
Bertie Gottgens |
| Organization name |
University of Cambridge
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| Department |
Haematology
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| Street address |
Hills Road
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| City |
Cambridge |
| ZIP/Postal code |
CB2 0XY |
| Country |
United Kingdom |
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| Platforms (2) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (2557)
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| Relations |
| BioProject |
PRJNA862285 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE209742_Patel_LSK_raw_Submission.h5ad.gz |
44.9 Mb |
(ftp)(http) |
H5AD |
| GSE209742_RAW.tar |
100.9 Mb |
(http)(custom) |
TAR (of H5) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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