Single-cell RNA-seq reveals a concomitant delay in differentiation and cell cycle of aged hematopoietic stem cells

Abstract

Background Hematopoietic stem cells (HSCs) are the guarantor of the proper functioning of hematopoiesis due to their incredible diversity of potential. During aging, heterogeneity of HSCs changes, contributing to the deterioration of the immune system. In this study, we revisited mouse HSC compartment and its transcriptional plasticity during aging at unicellular scale. Results Through the analysis of 15,000 young and aged transcriptomes, we identified 15 groups of HSCs revealing rare and new specific HSC abilities that change with age. The implantation of new trajectories complemented with the analysis of transcription factor activities pointed consecutive states of HSC differentiation that were delayed by aging and explained the bias in differentiation of older HSCs. Moreover, reassigning cell cycle phases for each HSC clearly highlighted an imbalance of the cell cycle regulators of very immature aged HSCs that may contribute to their accumulation in an undifferentiated state. Conclusions Our results establish a new reference map of HSC differentiation in young and aged mice and reveal a potential mechanism that delays the differentiation of aged HSCs and could promote the emergence of age-related hematologic diseases.

Inflammation and Aging of Hematopoietic Stem Cells in Their Niche

“…Consistently, PU.1-deficient HSCs displayed overexpressed cell cycle and protein synthesis genes [82]. Aged HSCs display cell cycle arrest [90,91], which is associated with replicative stress [90]. Further studies are needed to investigate to what extent the dormant status of aged HSCs is caused by chronic exposure to inflammation.…”

Aging and Clonal Behavior of Hematopoietic Stem Cells

“…These results point to the age-related expansion of HSC clones with relative resistance to differentiation-instructing stimuli, and although these latent HSCs are essentially defined by transplantation experiments, it is possible that they may also be childless in the native hematopoiesis of aged organisms (Figure 2d). The heterogeneity of aged HSCs is also demonstrated in terms of transcriptome [53,[61][62][63],…”

A novel Boolean network inference strategy to model early hematopoiesis aging

“…We used the Single-Cell Regulatory Network Inference and Clustering (SCENIC) approach 19 to identify regulons, which are modules of one TF and its potential targets, and their activities. We ran SCENIC workflow using pySCENIC v1.10.0 with its command line implementation 21 as in our previous study regarding gene filtering, TF motifs (motifs-v9-nr.mgi-m0.001-o0.0), cis-target (+/-10 kb from TSS mm9-tss-centered-10 kb-7species.mc9nr) databases and command line options 1 . In this study we used the whole 1721 TFs with an available motif in the motif database as input.…”

“… Abstract We previously analyzed 15 000 transcriptomes of mouse hematopoietic stem and progenitor cells (HSPCs) from young and aged mice and characterized the early differentiation of the hematopoietic stem cells (HSCs) according to age, thanks to cell clustering and pseudotime analysis 1 . In this study, we propose an original strategy to build a Boolean gene network explaining HSC priming and homeostasis based on our previous single cell data analysis and the actual knowledge of these biological processes (graphical abstract) .We first made an exhaustive analysis of the transcriptional network on selected HSPC states in the differentiation trajectory of HSCs by identifying regulons, modules formed by a transcription factor (TFs) and its targets, from the scRNA-seq data., From this global view of transcriptional regulation in early hematopoiesis, we chose to focus on 15 components, 13 selected TFs (Tal1, Fli1, Gata2, Gata1, Zfpm1, Egr1, Junb, Ikzf1, Myc, Cebpa, Bclaf1, Klf1, Spi1) and two complexes regulating the ability of HSC to cycle (CDK4/6 - Cyclines D and CIP/KIP).…”