REVIEWS The ageing haematopoietic stem cell compartment Hartmut Geiger1,2, Gerald de Haan3 and M. Carolina Florian1 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. HSC niche The current demographic shift towards an ageing popu- The innate immune system is also affected by ageing. A specialized lation is an unprecedented global phenomenon that has Although an increase in the number of myeloid precur- microenvironment that profound implications. Ageing is associated with tissue sors has been described in the bone marrow of elderly interacts with haematopoietic attrition and an increased incidence of many types of can- people, the oxidative burst and the phagocytic capacity of stem cells (HSCs) to regulate cers, including both myeloid and lymphoid leukaemias, and both macrophages and neutrophils are decreased in these their fate. other haematopoietic cell malignancies1,2. Thus, we need individuals12,13. Moreover, the levels of soluble immune to understand the molecular and cellular mechanisms of mediators are altered with ageing. Elevated plasma con- ageing to attenuate ageing-associated tissue attrition and centrations of several cytokines, such as interleukin‑6 disease, and to improve the quality of life for the elderly. (IL‑6), tumour necrosis factor and IL‑1β, have been Alterations that affect the immune system — globally described as predictive markers for morbidity and mortal- referred to as immunosenescence — are among the fac- ity in the elderly. These factors are thought to result in an 1Department of Dermatology tors associated with ageing that reduce the quality of life ageing-associated subclinical inflammatory status, which and Allergic Diseases, for the elderly. Age-related changes in the immune system has also been described as ‘inflamm-ageing’ and drives University of Ulm, 89091 contribute to the increased susceptibility of the elderly to the development and progression of age-related diseases Ulm, Germany. infectious diseases, autoimmunity, anaemia, vaccine fail- such as osteoporosis and neurodegenerative disorders14. 2 Division of Experimental 2–5 Hematology and Cancer ure and, possibly, cancers such as leukaemia . Many The dysfunction of haematopoietic stem cells (HSCs), Biology, Cincinnati Children’s of these ageing-related pathologies can be attributed to which give rise to both myeloid and lymphoid lineages, Hospital Medical Center, the ageing of the adaptive immune system. For example, the might underlie the ageing of the innate and adaptive Department of Pediatrics, peripheral B cell pool fills up with memory cells in elderly immune systems. Indeed, there is now growing evidence University of Cincinnati, individuals, and this results in limited diversity in the that the ageing of the immune system is initiated at the Cincinnati, Ohio 45229, USA. 3Ageing Biology and Stem B cell repertoire, reduced effectiveness of vaccination, and very top of the haematopoietic hierarchy. For example, Cells group, Department of an age-related increase in circulating autoreactive anti- B cell lymphopoiesis is directly affected by HSC ageing, Biology of Ageing, European bodies3,4. The number of naive T cells decreases considera- and an ageing-associated reduction in the generation of Research Institute for the bly with age, which is partly linked to the involution of the B cell precursors has been linked to impaired function Biology of Ageing, University 6,7 12,15,16 Medical Center Groningen, thymus . The defective generation of naive T cells, and of aged HSCs . University of Groningen, the accumulation of effector and memory T cells, results In adults, HSCs reside primarily in the bone marrow 9713 AV Groningen, in decreased diversity in the T cell repertoire after the age within a specialized microenvironment called the The Netherlands. of 70 (REFS 8,9). As changes in the T cell compartment HSC niche. The HSC niche provides soluble factors and Correspondence to H.G. precede the ageing-associated changes in the B cell com- cell–cell interactions that are crucial for regulating HSC e-mail: self-renewal (BOX 1) [email protected] partment, it is thought that T cells fail to sustain B cell and differentiation . In the adult bone doi:10.1038/nri3433 proliferation and high-affinity antibody production in marrow there is a low frequency of HSCs, with two Published online 15 April 2013 elderly individuals10,11. to five HSCs per 105 total bone marrow cells17,18. 376 | MAY 2013 | VOLUME 13 www.nature.com/reviews/immunol © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS Box 1 | The HSC niche What separates young from aged HSCs? There are several generally accepted functional, cellular The bone marrow microenvironment provides regions that support the function of and molecular criteria that can be used to distinguish haematopoietic stem cells (HSCs) and other types of haematopoietic cells, including between young and aged HSCs. In this section, we monocytes and lymphocytes. Cells within these regions constitute the HSC niche116 summarize and interpret the HSC phenotypes that are (see figure). The HSC niche contributes to the control of HSC quiescence, proliferation, self-renewal and differentiation. The niche within the bone consists of a network of associated with ageing and suggest a set of criteria that vessels, nerve fibres, bone remodelling cells and subpopulations of haematopoietic should be used to define the phenotype of aged HSCs cells, which result in a complex three-dimensional architecture44,46,100,135–137. These niche (FIG. 1). As ageing is a gradual process, ageing-associated functions are mediated by crosstalk between niche cells and HSCs. Novel research phenotypes are sometimes ambiguous; although some indicates that this signal exchange is multidirectional and multidimensional136. Signals distinct phenotypes can help to clearly distinguish between the niche cells and HSCs can be transmitted via direct cell–cell contact between young and aged HSCs, there is also a range of (through adhesion receptors46 and gap junctions such as connexin 43 junctions)109–111, phenotypes on the basis of which HSCs cannot always cytokines and chemokines (such as CXC-chemokine ligand 12 (CXCL12; also known as be easily classified as young or aged. SDF1))138, growth factors and via components of the extracellular matrix (such as fibronectin). HSCs often reside close to the endosteum (the endosteal niche) and the Increased HSC numbers and decreased regenerative vascular system (the vascular niche) in the bone marrow. In these niches, HSCs are in close proximity to reticular cells expressing high levels of CXCL12 (CXCL12‑abundant potential. Stem cells are often considered to be a ‘fountain reticular cells; CAR cells), Schwann-like cells and nestin-positive mesenchymal stem of eternal youth’ because of their capacity for self-renewal cells (NES+ MSCs), which are all closely surrounded by nerve fibres139. Niches comprise and their differentiation potential. So, it seems likely that non-haematopoietic cells, such as endothelial cells, osteoblasts and osteoclasts, loss of stem cell activity underlies ageing-associated adipocytes and MSCs, but haematopoietic cells (mainly macrophages) also contribute tissue attrition. to niche function140. Research performed over the past few decades now Adipocyte enables HSCs to be phenotypically identified on the Osteoclast basis of several sets of cell surface markers, in both Osteoblast humans and mice (TABLE 1). Unexpectedly, the number of such phenotypically defined HSCs in the bone mar- row increases by two- to tenfold with ageing, regard- Adhesion less of which distinct sets of cell surface markers are molecules used to define HSCs, in both mice and humans19–26 CAR cell NES+ MSC (TABLE 1). Intuitively, the increased HSC numbers that HSC are observed in elderly individuals are considered to be Gap junction Endosteal niche beneficial, as these HSCs might, for example, sustain immune functions. Nevertheless, under conditions of Sympathetic Extracellular stress and regeneration, as in serial transplantation assays, nerve Macrophage matrix aged HSCs exhibit several functional defects, including HSC Endothelial cell a diminished regenerative potential, as a result of their reduced long-term self-renewal capacity. The increase Perivascular in the number of HSCs does not compensate for their CAR cell loss in function, and this leads to an overall reduction Cytokines Sinusoid in the regenerative capacity of the pool of aged HSCs27 and growth (FIG. 1). This is particularly evident when purified stem factors cell populations are analysed25,28. Perivascular niche Perivascular The mechanisms that underlie the ageing-associated HSC increase in HSC numbers are still poorly understood, even though this aspect of HSC biology has been Schwann-like cell known for a long time. It has been proposed