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.

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

10.1101/2020.06.17.156893 ◽

2020 ◽

Author(s):

Léonard Hérault ◽

Mathilde Poplineau ◽

Adrien Mazuel ◽

Nadine Platet ◽

Élisabeth Remy ◽

...

Keyword(s):

Cell Cycle ◽

Single Cell ◽

Single Cell Level ◽

Cell Cycle Regulators ◽

Potential Mechanism ◽

Rna Seq ◽

Cell Level ◽

Hematopoietic Stem ◽

Undifferentiated State ◽

Reference Map

ABSTRACTHematopoietic stem cells (HSCs) are the guarantor of the proper functioning of hematopoiesis due to their incredible diversity of potential. During aging the heterogeneity of mouse HSCs evolves, which contributes to the deterioration of the immune system. Here we address the transcriptional plasticity of HSC upon aging at the single-cell resolution. Through the analysis of 15,000 young and aged transcriptomes, we reveal 15 clusters of HSCs unveiling rare and specific HSC abilities that change with age. Pseudotime ordering complemented with regulon analysis showed that the consecutive differentiation states of HSC are delayed upon aging. By analysing cell cycle at the single cell level we highlight an imbalance of cell cycle regulators of very immature aged HSC that may contribute to their accumulation in an undifferentiated state.Our results therefore establish a reference map of young and old mouse HSC differentiation and reveal a potential mechanism that delay aged HSC differentiation.

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Sustained PU.1 Levels Balance Cell-Cycle Regulators to Prevent Exhaustion of Adult Hematopoietic Stem Cells

Molecular Cell ◽

10.1016/j.molcel.2013.01.007 ◽

2013 ◽

Vol 49 (5) ◽

pp. 934-946 ◽

Cited By ~ 67

Author(s):

Philipp B. Staber ◽

Pu Zhang ◽

Min Ye ◽

Robert S. Welner ◽

César Nombela-Arrieta ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Hematopoietic Stem Cells ◽

Cell Cycle Regulators ◽

Hematopoietic Stem

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

Genome Research ◽

10.1101/gr.192237.115 ◽

2015 ◽

Vol 25 (12) ◽

pp. 1860-1872 ◽

Cited By ~ 280

Author(s):

Monika S. Kowalczyk ◽

Itay Tirosh ◽

Dirk Heckl ◽

Tata Nageswara Rao ◽

Atray Dixit ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Hematopoietic Stem Cells ◽

Single Cell ◽

Rna Seq ◽

Hematopoietic Stem

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

BMC Biology ◽

10.1186/s12915-021-01005-4 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Léonard Hérault ◽

Mathilde Poplineau ◽

Adrien Mazuel ◽

Nadine Platet ◽

Élisabeth Remy ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Hematopoietic Stem Cells ◽

Single Cell ◽

Rna Seq ◽

Hematopoietic Stem

An amendment to this paper has been published and can be accessed via the original article.

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Faculty Opinions recommendation of Sustained PU.1 levels balance cell-cycle regulators to prevent exhaustion of adult hematopoietic stem cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717977318.793471188 ◽

2013 ◽

Author(s):

Stephen Nutt

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Hematopoietic Stem Cells ◽

Cell Cycle Regulators ◽

Hematopoietic Stem

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Control of self-renewal and differentiation of hematopoietic stem cells by negative cell-cycle regulators

Experimental Hematology ◽

10.1016/j.exphem.2007.01.016 ◽

2007 ◽

Vol 35 (4) ◽

pp. 94-95

Author(s):

Carl Walkley

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Hematopoietic Stem Cells ◽

Cell Cycle Regulators ◽

Self Renewal ◽

Hematopoietic Stem ◽

Negative Cell

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Single cell RNA-Seq of hematopoietic stem cells reveals a cell cycle-dependent interplay between aging and differentiation

Experimental Hematology ◽

10.1016/j.exphem.2014.07.075 ◽

2014 ◽

Vol 42 (8) ◽

pp. S21

Author(s):

Monika Kowalczyk ◽

Itay Tirosh ◽

Dirk Heckl ◽

Benjamin Ebert ◽

Aviv Regev

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Hematopoietic Stem Cells ◽

Single Cell ◽

Rna Seq ◽

Hematopoietic Stem ◽

A Cell ◽

Cycle Dependent

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Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli are Altered with Age

10.1101/163402 ◽

2017 ◽

Cited By ~ 2

Author(s):

Mati Mann ◽

Arnav Mehta ◽

Carl de Boer ◽

Monika S. Kowalczyk ◽

Kevin Lee ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Rna Seq ◽

Hematopoietic Stem ◽

Inflammatory Stress ◽

Age Related ◽

Inflammatory Stimuli ◽

A Cell ◽

Expression Program

Long-term hematopoietic stem cells (LT-HSCs) maintain hematopoietic output throughout an animal's lifespan. With age, however, they produce a myeloid-biased output that may lead to poor immune responses to infectious challenge and the development of myeloid leukemias. Here, we show that young and aged LT-HSCs respond differently to inflammatory stress, such that aged LT-HSCs produce a cell-intrinsic, myeloid-biased expression program. Using single-cell RNA-seq, we identify a myeloid-biased subset within the LT-HSC population (mLT-HSCs) that is much more common amongst aged LT-HSCs and is uniquely primed to respond to acute inflammatory challenge. We predict several transcription factors to regulate differentially expressed genes between mLT-HSCs and other LT-HSC subsets. Among these, we show that Klf5, Ikzf1 and Stat3 play important roles in age-related inflammatory myeloid bias. These factors may regulate myeloid versus lymphoid balance with age, and can potentially mitigate the long-term deleterious effects of inflammation that lead to hematopoietic pathologies.

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