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Single Cell RNA-Sequencing using smart-seq2 of young and old murine hematopoietic stem cells

ABSTRACT: Ageing of the hematopoietic stem cell (HSC) compartment is characterized by skewing towards the myeloid lineage and reduced stem cell function, the molecular basis of which is largely unknown. Using single cell approaches we identify features contributing to HSC exhaustion with age. A distinct subpopulation of old HSCs carried a signature indicative of impaired stem cell function, activating p53 targets involved in senescence. In the same HSCs, we identified pro-proliferative JAK/STAT and MAPK signalling. We hypothesized that prolonged proliferation of HSCs leads to cell cycle arrest with age and therefore challenged HSCs with a constant proliferative stimulus mediated by a constitutively active form of Jak2, Jak2V617F. Indeed we observed expansion of the p53 positive population and functional impairment of the challenged HSCs. Our results reveal unexpected heterogeneity in the rate of HSC ageing and strongly implicate a role for proliferation in the p53 mediated functional decline of old HSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE87631 | GEO | 2017/05/22

SECONDARY ACCESSION(S): PRJNA345438

REPOSITORIES: GEO

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