Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells

TLDR

Aging of hematopoietic stem cells is driven by intrinsic state changes and shifts in stem cell population composition. Single‑cell RNA‑seq was applied to HSCs and progenitors from young and old mice of two strains to resolve population variability. Old long‑term HSCs exhibit reduced G1 frequency and faster G1 progression, while aged short‑term HSCs resemble young long‑term HSCs transcriptionally, indicating that aging shifts HSCs toward a less differentiated state and links altered cell‑cycle dynamics to impaired self‑renewal and differentiation.

Abstract

Both intrinsic cell state changes and variations in the composition of stem cell populations have been implicated as contributors to aging. We used single-cell RNA-seq to dissect variability in hematopoietic stem cell (HSC) and hematopoietic progenitor cell populations from young and old mice from two strains. We found that cell cycle dominates the variability within each population and that there is a lower frequency of cells in the G1 phase among old compared with young long-term HSCs, suggesting that they traverse through G1 faster. Moreover, transcriptional changes in HSCs during aging are inversely related to those upon HSC differentiation, such that old short-term (ST) HSCs resemble young long-term (LT-HSCs), suggesting that they exist in a less differentiated state. Our results indicate both compositional changes and intrinsic, population-wide changes with age and are consistent with a model where a relationship between cell cycle progression and self-renewal versus differentiation of HSCs is affected by aging and may contribute to the functional decline of old HSCs.