Differences in Cell Cycle Status Underlie Transcriptional Heterogeneity in the HSC Compartment

Cell Reports
Felicia Kathrine Bratt LauridsenBo Torben Porse

Abstract

Hematopoietic stem cells (HSCs) are considered a heterogeneous cell population. To further resolve the HSC compartment, we characterized a retinoic acid (RA) reporter mouse line. Sub-fractionation of the HSC compartment in RA-CFP reporter mice demonstrated that RA-CFP-dim HSCs were largely non-proliferative and displayed superior engraftment potential in comparison with RA-CFP-bright HSCs. Gene expression analysis demonstrated higher expression of RA-target genes in RA-CFP-dim HSCs, in contrast to the RA-CFP reporter expression, but both RA-CFP-dim and RA-CFP-bright HSCs responded efficiently to RA in vitro. Single-cell RNA sequencing (RNA-seq) of >1,200 HSCs showed that differences in cell cycle activity constituted the main driver of transcriptional heterogeneity in HSCs. Moreover, further analysis of the single-cell RNA-seq data revealed that stochastic low-level expression of distinct lineage-affiliated transcriptional programs is a common feature of HSCs. Collectively, this work demonstrates the utility of the RA-CFP reporter line as a tool for the isolation of superior HSCs.

Citations

May 16, 2019·Journal of Zhejiang University. Science. B·Su-Wei Gao, Feng Liu
Nov 7, 2019·World Journal of Stem Cells·Xiao Zhang, Lei Liu
Jul 17, 2020·Nature·Alejo E Rodriguez-FraticelliFernando D Camargo
Sep 12, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Shi-Lei ZhangTao Liu
Mar 7, 2021·International Journal of Molecular Sciences·Matthias Mietsch, Rabea Hinkel
Jun 9, 2021·Nature Communications·Erwin M SchoofBo T Porse
Aug 27, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Ziqing LiuVictoria L Bautch
Dec 22, 2021·Nucleic Acids Research·Jiajia LiuXiaobo Zhou

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