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The ageing haematopoietic stem cell compartment

Subjects

Key Points

  • The ageing of the immune system is initiated at the very top of the haematopoietic hierarchy, and the ageing of haematopoietic stem cells (HSCs) directly contributes to changes in the immune system.

  • In this Review, the authors summarize the phenotypes of ageing HSCs and discuss how the cell-intrinsic and cell-extrinsic mechanisms of HSC ageing might promote immunosenescence. Loss of polarity in HSCs mediated by increased activity of the RHO GTPase cell division control protein 42 (CDC42) is a novel ageing-associated phenotype in HSCs.

  • The relevance of epigenetic stability in stem cell ageing is only now beginning to emerge. Changes in the epigenetic landscape of HSCs upon ageing might be involved in the ageing of stem cells.

  • Moreover, new research supports the idea that the ageing of the stem cell niche contributes to the ageing of HSCs.

  • The ageing of HSCs can be ameliorated, for example, by pharmacological inhibition of CDC42 or by targeting the mammalian target of rapamycin (mTOR) pathway.

  • Several questions and controversies remain in stem cell ageing research. Dissecting the causes and the consequences of HSC ageing remains a major challenge.

Abstract

Stem cell ageing underlies the ageing of tissues, especially those with a high cellular turnover. There is growing evidence that the ageing of the immune system is initiated at the very top of the haematopoietic hierarchy and that the ageing of haematopoietic stem cells (HSCs) directly contributes to changes in the immune system, referred to as immunosenescence. In this Review, we summarize the phenotypes of ageing HSCs and discuss how the cell-intrinsic and cell-extrinsic mechanisms of HSC ageing might promote immunosenescence. Stem cell ageing has long been considered to be irreversible. However, recent findings indicate that several molecular pathways could be targeted to rejuvenate HSCs and thus to reverse some aspects of immunosenescence.

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Figure 1: Phenotypical and functional changes in HSCs upon ageing.
Figure 2: Cell-intrinsic mechanisms of HSC ageing.
Figure 3: The contribution of the niche to HSC ageing.

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Acknowledgements

The authors apologize to those researchers whose work could not be discussed or referenced owing to space limitations. The work in the laboratory of H. Geiger is supported by grants from the Deutsche Forschungsgemeinschaft, Germany (KFO 142, GE2063/1 and SFB 1074); the German Federal Ministry of Education and Research (SyStaR); the excellence programme of the Baden-Württemberg Foundation, Germany; the US National Institutes of Health (HL076604, DK077762 and AG040118); the Edward P. Evans foundation, USA; the European Commission (FP7 Marie Curie Initial Training Network MARRIAGE) and a “Bausteinprogramm” from the Department of Medicine, University of Ulm, Germany, awarded to M. C. Florian. Work in the laboratory of G. de Haan is supported by grants from the Netherlands Institute for Regenerative Medicine (NIRM), the European Commission (FP7 Marie Curie Initial Training Networks EuroCancerCSC, HaEM-ID and MARRIAGE) and the Mouse Clinic for Cancer and Ageing (MCCA) funded by the Netherlands Organization for Scientific Research. The authors thank N. Guidi for her contribution to the manuscript.

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Glossary

HSC niche

A specialized microenvironment that interacts with haematopoietic stem cells (HSCs) to regulate their fate.

Self-renewal

The capacity to recreate stem cells with differentiation potentials that are similar to those of the mother stem cell. Self-renewal can result from either an asymmetric cell division that yields a daughter stem cell and a cell committed to differentiation, or from a symmetric cell division that yields two daughter stem cells. Alternatively, stem cell differentiation can result in the loss of self-renewal capacity.

Serial transplantation assays

Assays used to test the ability of haematopoietic stem cells (HSCs) to undergo self-renewal. The number of serial transplantations that the original donor's bone marrow can perform successfully is a measure of the self-renewal capacity of the HSCs it contains. The serial transplantation of defined numbers of purified HSCs allows the normalization of differences in stem cell frequencies among mice of different ages and offers a more controlled 'per cell' readout than serial transplantation of unfractionated bone marrow cells.

Symmetric cell divisions

Stem cell divisions in which the two daughter cells are identical with respect to function and differentiation potential.

Common lymphoid progenitor

(CLP). A progenitor that is committed to the lymphoid lineage and can give rise to all lymphocyte subsets, including T cells, B cells and natural killer cells. CLP cells are defined as FLK2+IL-7Rα+KITlow/hi SCA1low/hiLIN in mice, and LINCD34+CD38+CD127+ in humans.

Common myeloid progenitor

(CMP). A progenitor that is committed to the myeloid lineage and can give rise to all myeloid subsets, including neutrophils, basophils, monocytes and platelets. CMP cells are defined as LINIL-7RαSCA1KIT+FcRIlowCD34+ in mice and LINCD34+CD38+ CD123+CD45RA in humans.

Bone marrow homing

The process whereby haematopoietic stem cells (HSCs) migrate from the circulation to the HSC niche. Homing is distinct from lodgement, which is the ability of HSCs to enter the niche and stay there, as well as from engraftment, which is the ability of HSCs to respond to appropriate maintenance and differentiation signals when they are lodged.

Quiescence

A non-cycling resting state in the G0 phase of the cell cycle that is important for long-term function.

Reactive oxygen species

(ROS). Highly reactive molecules that consist of several diverse chemical species including the superoxide anion (O2•−), hydroxyl radical (OH) and hydrogen peroxide (H2O2). Because of their potential to cause oxidative deterioration of DNA, proteins and lipids, ROS have been implicated as one of the causative factors of ageing. As ROS are generated mainly as by-products of mitochondrial respiration, mitochondria are thought to be the primary target of oxidative damage.

Replicative senescence

An inability of most cell types to divide indefinitely owing to terminal cell cycle arrest after a defined number of cell cycles, probably as a result of telomere attrition.

Mammalian target of rapamycin

(mTOR). A conserved serine/threonine kinase regulating metabolism and the expression of growth factors in response to environmental cues. mTOR activity is inhibited by the drug rapamycin.

FOXO protein family

A subgroup of the forkhead box (FOX) family of transcription factors. FOXO proteins are regulated by the insulin–phosphoinositide 3-kinase–AKT signalling pathway.

Telomere

A repetitive nucleotide sequence at the end of chromosomes that protects the ends from deterioration or from fusion with neighbouring chromosomes.

Telomerase

An enzyme that is capable of extending the ends of telomeres after replication using an RNA template that is part of the enzyme complex. This counteracts telomere shortening after each cell division cycle.

H2AX

Histone 2A family, member X; phosphorylated H2AX is a sensitive marker for DNA double-strand breaks. Almost every DNA double-strand break forms a H2AX focus, but whether every H2AX focus identifies a double-strand break remains controversial.

p53

A tumour suppressor protein that responds to diverse cellular stresses by regulating target genes that induce cell cycle arrest, apoptosis, senescence, DNA repair or changes in metabolism.

p16INK4A

A cyclin-dependent kinase inhibitor that stabilizes cell cycle arrest by activating the checkpoint activity of the retinoblastoma protein.

BCL-2 family

A family of proteins containing at least one BCL-2 homology (BH) region. The family is divided into anti-apoptotic multidomain proteins (such as BCL-2 and BCL-XL), which contain four BH domains (BH1, BH2, BH3 and BH4), pro-apoptotic multidomain proteins (for example, BAX and BAK), which contain BH1, BH2 and BH3 domains, and the pro-apoptotic BH3-only family (such as BH3-interacting-domain death agonist (BID), BCL-2-interacting mediator of cell death (BIM) and p53-upregulated modulator of apoptosis (PUMA)).

Epigenetic information

Non-genetic information that promotes alternative cell states and is regulated by developmental and environmental cues. Epigenetic information maintains distinct phenotypes among cells that share identical DNA sequences.

DNA methyltransferases

(DNMTs). Enzymes that transfer methyl groups from S-adenosylmethionine to specific adenines or cytosines in DNA.

Histone methyltransferases

Enzymes that catalyse the transfer of methyl groups to lysine and/or arginine residues on histones; the most well-studied histone methyltransferase is SUV39H1 (suppressor of variegation B9 homolog 1) and its mammalian homologues, which methylate histone H3 on lysine 9.

SWI/SNF complex

An ATP-dependent chromatin-remodelling protein complex that was initially identified in yeast. Related complexes exist in mammals and are involved in the remodelling of chromatin in various genes.

Polycomb repressive complexes

(PRCs). Groups of proteins that maintain gene expression states throughout development by regulating chromatin structure. In mammals there are two core Polycomb complexes: PRC1 and PRC2. PRC1 catalyses the monoubiquitylation of histone H2A. Both complexes contribute to chromatin compaction. PRC2 harbours the histone methyltransferases EZH1 (enhancer of zeste homolog 1) and EZH2, which catalyse the methylation of histone H3 at lysine 27. These two complexes are involved in differentiation, in the maintenance of cell identity and proliferation, and in stem cell plasticity.

H3K4 trimethylation complex

A complex of proteins that are involved in the addition of three methyl groups to histone H3 on lysine 4.

Cell polarity

The asymmetric distribution of proteins, lipids and/or their complexes within the cell. It is believed that polarity determines the mode of cell division and thus the fate of the two daughter cells.

Centrosomes

Cytoplasmic organelles that organize the microtubules. Preceding mitosis, the centrosome doubles and is then involved in the generation of the mitotic spindle for subsequent chromosome segregation during mitosis. In many cell types the centrosome is directly located in the centre of the cell and is therefore assigned a polar distribution, in which case cells frequently undergo asymmetric divisions.

Mode of stem cell division

An symmetric or asymmetric event, with respect to the potential of the daughter cells. An asymmetric division balances stem cell self-renewal and differentiation through the production of one stem cell and one differentiating cell, whereas a symmetric division might result in either two stem cells or two differentiated cells.

Osteoblasts

Cells of mesenchymal origin that are responsible for the formation of bone. Osteoblasts are thought to be a crucial component of the haematopoietic stem cell niche.

Mesenchymal stem cells

(MSCs). Multipotent progenitor cells originally identified in the bone marrow stroma. MSCs can be expanded in vitro and, under appropriate conditions, give rise to several cell types, including bone and fat precursors.

Gap junction channels

Channels composed of integral membrane proteins called connexins. Gap junction channels connect the cytoplasms of adjacent cells, allowing for the diffusion of ions and small metabolites between cells.

CCL11

CC-chemokine ligand 11; a member of the CC-chemokine family and selectively recruits eosinophils. Increased CCL11 levels in the blood are found in aged mice and humans.

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Geiger, H., de Haan, G. & Florian, M. The ageing haematopoietic stem cell compartment. Nat Rev Immunol 13, 376–389 (2013). https://doi.org/10.1038/nri3433

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