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

TY - JOUR

T1 - Differences in Cell Cycle Status Underlie Transcriptional Heterogeneity in the HSC Compartment

AU - Lauridsen, Felicia KB.

AU - Jensen, Tanja L.

AU - Rapin, Nicolas

AU - Aslan, Derya

AU - Wilhelmson, Anna S.

AU - Pundhir, Sachin

AU - Rehn, Matilda

AU - Paul, Franziska

AU - Giladi, Amir

AU - Hasemann, Marie Sigurd

AU - Serup, Palle

AU - Amit, Ido

AU - Porse, Bo Torben

N1 - Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2018/7/17

Y1 - 2018/7/17

N2 - 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. HSCs are considered a functional heterogeneous population. Lauridsen et al. use scRNA-seq to demonstrate that most transcriptional heterogeneity within the HSC compartment is associated with differences in cell cycle status. They further use an RA-CFP reporter mouse line to isolate slow-cycling HSCs characterized by superior engraftment potential.

AB - 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. HSCs are considered a functional heterogeneous population. Lauridsen et al. use scRNA-seq to demonstrate that most transcriptional heterogeneity within the HSC compartment is associated with differences in cell cycle status. They further use an RA-CFP reporter mouse line to isolate slow-cycling HSCs characterized by superior engraftment potential.

U2 - 10.1016/j.celrep.2018.06.057

DO - 10.1016/j.celrep.2018.06.057

M3 - Journal article

C2 - 30021172

SN - 2211-1247

VL - 24

SP - 766

EP - 780

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -