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Adult haematopoietic stem cell niches

Key Points

  • Dividing and non-dividing haematopoietic stem cells (HSCs) reside in perivascular niches that are mainly associated with sinusoidal blood vessels in adult bone marrow and spleen.

  • A subset of HSCs is most closely associated with arterioles. The periarteriolar and perisinusoidal microenvironments differ in terms of the capacity of HSCs to intravasate into the circulation and in terms of their exposure to blood plasma components.

  • Endothelial cells and leptin receptor-expressing, CXC-chemokine ligand 12 (CXCL12)-abundant reticular perivascular stromal cells are the main sources of the stem cell factor (SCF) and CXCL12 required for HSC maintenance in normal young-adult bone marrow. Other perivascular cells, such as Ng2-CreER+ periarteriolar cells (which express neural–glial antigen 2), may or may not also synthesize the CXCL12 required for HSC maintenance.

  • Several other cell types — including megakaryocytes, monocytes and macrophages, neurons (specifically, nerve fibres) and Schwann cells — directly or indirectly regulate HSC or niche function through other mechanisms.

  • Extramedullary haematopoiesis in the spleen depends on a perivascular niche that is associated with sinusoids in the red pulp, in which endothelial cells and transcription factor 21-expressing stromal cells are the main sources of SCF and CXCL12. This niche is necessary for the recovery of haematopoiesis from haematopoietic stresses such as blood loss.

  • The vascular and stromal compositions of the bone marrow change during ageing.

Abstract

Stem cell niches are specialized microenvironments that promote the maintenance of stem cells and regulate their function. Recent advances have improved our understanding of the niches that maintain adult haematopoietic stem cells (HSCs). These advances include new markers for HSCs and niche cells, systematic analyses of the expression patterns of niche factors, genetic tools for functionally identifying niche cells in vivo, and improved imaging techniques. Together, they have shown that HSC niches are perivascular in the bone marrow and spleen. Endothelial cells and mesenchymal stromal cells secrete factors that promote HSC maintenance in these niches, but other cell types also directly or indirectly regulate HSC niches.

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Figure 1: The vasculature in the bone marrow and its relationship to HSCs.
Figure 2: The expression of stem cell factor in the bone marrow.
Figure 3: A schematic of the HSC niche in adult bone marrow.
Figure 4: Changes in the bone marrow vasculature with age.

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Acknowledgements

The authors apologize to those whose work could not be included owing to space limitations. S.J.M. is a Howard Hughes Medical Institute Investigator; the Mary McDermott Cook Chair in Pediatric Genetics; the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research; and the Director of the Hamon Laboratory for Stem Cells and Cancer at the University of Texas Southwestern Medical Center, USA. G.M.C. was supported by the University of Texas Southwestern Medical Center Physician Scientist Training Program. E.J. is a postdoctoral fellow of the Damon Runyon Cancer Research Foundation. This work was supported by the Cancer Prevention and Research Institute of Texas, USA, and by the US National Institutes of Health (grants R37 AG024945 and R01 DK100848).

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Glossary

Haematopoiesis

The process by which blood cells and immune system cells — including erythrocytes, platelets and white blood cells — are formed from haematopoietic stem cells, which undergo lineage restriction and then differentiation by giving rise to various restricted haematopoietic progenitors.

HSC transplantation

A potentially curative therapy involving the replacement of a patient's blood-forming cells with those from a donor (allogeneic) or with their own cells (autologous) that had been stored before chemotherapy or radiation treatment. This procedure can be carried out by transplanting whole bone marrow cells or enriched populations of haematopoietic stem cells (HSCs), which can be obtained from various sources, including bone marrow, mobilized peripheral blood or umbilical cord blood.

Conditioning regimen

Chemotherapy and/or radiation that ablates endogenous haematopoietic cells before haematopoietic stem cell (HSC) transplantation to facilitate the engraftment of the transplanted HSCs.

Ex vivo expansion

Increasing the number of haematopoietic stem cells (HSCs) that are available for transplantation by growing them in culture. For reasons that are not currently understood, it is not yet possible to considerably or sustainably increase the numbers of HSCs in culture, despite decades of effort.

Signalling lymphocyte activation molecule family markers

(SLAM family markers). A group of cell-surface receptors (including CD150, CD48, CD229 and CD244) that are differentially expressed among haematopoietic stem cells (HSCs) and other haematopoietic progenitors in a manner that enables them to be used to identify HSCs and multipotent progenitors.

Sinusoidal blood vessels

Fenestrated venous blood vessels that are found in haematopoietic tissues and through which haematopoietic cells can migrate into and out of the circulation.

Perivascular niche

A microenvironment in the bone marrow that is located adjacent to a blood vessel and that supports the maintenance of haematopoietic stem cells and/or other haematopoietic progenitors.

Ctnnal1-GFP knock-in mice

A gene-targeted mouse line in which green fluorescent protein (GFP) is knocked into the Ctnnal1 locus (which encodes α-catulin) such that GFP marks α-catulin+ cells, which are highly enriched for haematopoietic stem cells.

Arterioles

In the context of this Review, blood vessels of variable diameter that carry arterial blood into the bone marrow.

Transition zone vessels

In the context of this Review, small blood vessels that connect arterioles to sinusoids in the bone marrow and that are located near the endosteum.

Endosteum

The internal bone surface at the interface between bone and bone marrow.

Hoxb5-mCherry knock-in mice

A gene-targeted mouse line in which the fluorescence marker mCherry is knocked into the Hoxb5 locus (which encodes homeobox b5) such that mCherry marks Hoxb5+ cells, which are highly enriched for haematopoietic stem cells.

CXCL12-abundant reticular cells

(CAR cells). Stromal cells in the bone marrow that are mainly associated with sinusoidal blood vessels and that express high levels of CXC-chemokine ligand 12 (CXCL12), which is an important factor for retaining haematopoietic stem cells in the bone marrow niche.

Leptin receptor-expressing cells

(LEPR+ cells). Stromal cells in the bone marrow that are mainly associated with sinusoidal blood vessels and that express high levels of the crucial haematopoietic stem cell niche factors stem cell factor and CXC-chemokine ligand 12. These cells have commonly been identified using Lepr-Cre recombination systems, but in young-adult bone marrow nearly all of the bone marrow cells that recombine with Lepr-Cre also stain positively with LEPR-specific antibody.

Nes-CreER+ cells

Cells that express a tamoxifen-activated form of Cre recombinase under the control of regulatory elements of Nes (which encodes nestin). The conditional reporter is expressed by rare periarteriolar stromal cells in adult bone marrow but is more widely expressed in early postnatal bone marrow, where it shows widespread expression in endothelial cells, for example.

Ng2-CreER+ cells

Cells that express a tamoxifen-activated form of Cre recombinase from the Ng2 locus (which encodes neural–glial antigen 2). The conditional reporter is expressed by rare periarteriolar stromal cells in adult bone marrow but is much more widely expressed in early postnatal bone marrow.

Skeletal stem cells

(SSCs). A rare self-renewing stem cell population in the bone marrow that has the potential to form osteoblasts, adipocytes and chondrocytes, and that has the physiological function of maintaining the adult skeleton.

Schwann cells

Neural crest-derived cells that include myelinating and non-myelinating glia that are associated with peripheral nerve fibres in the bone marrow.

AMD3100

Also known as plerixafor. A CXC-chemokine receptor 4 (CXCR4) antagonist that is used to promote the mobilization of haematopoietic stem cells by reducing CXC-chemokine ligand 12 (CXCL12)–CXCR4 signalling.

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Crane, G., Jeffery, E. & Morrison, S. Adult haematopoietic stem cell niches. Nat Rev Immunol 17, 573–590 (2017). https://doi.org/10.1038/nri.2017.53

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