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Bone-marrow haematopoietic-stem-cell niches

Key Points

  • Haematopoietic stem cells (HSCs) have the clonal capacity to lifelong reconstitute all blood lineages after transplantation into lethally irradiated recipients, and are thought to be localized in a specific microenvironment called the niche.

  • An individual stem cell can give rise to two non-identical daughter cells, one maintaining stem-cell identity and the other becoming a differentiated cell. There are two mechanisms by which this asymmetry can be achieved, depending on whether it occurs pre- (divisional asymmetry), or post- (environmental asymmetry) cell division.

  • Adult stem cells are located in a specific stem-cell-fate-maintaining microenvironment called the niche. A stem-cell niche can be defined as a spatial structure in which stem cells are housed and maintained by allowing self-renewal in the absence of differentiation.

  • Bone-marrow HSCs and their niches are either located near the endosteal lining of the bone-marrow cavities (the endosteal niche) or are in close contact to the endothelium of the sinusoids (the vascular niche).

  • The endosteal niche comprises specialized osteoblastic cells. The physical interaction between HSCs and osteoblastic cells is mediated by a variety of cell-adhesion molecules including N-cadherin and members of the integrin family.

  • The tight physical interaction between HSCs and niche cells allows molecular crosstalk of ligand–receptor pairs including membrane-bound stem-cell factor (SCF)–KIT, angiopoietin-1 (ANG1)– tyrosine kinase receptor 2 (TIE2) and bone morphogenetic protein (BMP)–BMP-receptor-1A (BMPR1A), which on one hand maintain HSC fate and on the other hand preserve niche activity. We propose the term 'stem-cell–niche synapse' for this adhesion and signalling unit that controls HSC self-renewal and differentiation as well as stem-cell quiescence.

Abstract

Adult stem cells hold many promises for future clinical applications and regenerative medicine. The haematopoietic stem cell (HSC) is the best-characterized somatic stem cell so far, but in vitro expansion has been unsuccessful, limiting the future therapeutic potential of these cells. Here we review recent progress in characterizing the composition of the HSC bone-marrow microenvironment, known as the HSC niche. During homeostasis, HSCs, and therefore putative bone-marrow HSC niches, are located near bone surfaces or are associated with the sinusoidal endothelium. The molecular crosstalk between HSCs and the cellular constituents of these niches is thought to control the balance between HSC self-renewal and differentiation, indicating that future successful expansion of HSCs for therapeutic use will require three-dimensional reconstruction of a stem-cell–niche unit.

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Figure 1: A model of asymmetric cell division.
Figure 2: Different types of niche.
Figure 3: Model of bone-marrow HSC niches.
Figure 4: Mobilization, homing and lodging.
Figure 5: A model of the endosteal niche–stem-cell synapse.

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Acknowledgements

We would like to thank F. Radtke, R. MacDonald, M. Murphy and G. Oser for their critical reading of the manuscript, and members of the Trumpp Laboratory for helpful discussions. We apologize to colleagues whose work could not be cited due to space limitations. This work was in part supported by grants to A.T. from the Swiss National Science Foundation, the Swiss Cancer League and the UBS Optimus Foundation. A.T. is member of the EMBO Young Investigator Program.

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Glossary

Self-renewal

The capacity of a stem cell to divide in such a way that one or both daughter cells retain the stem-cell fate.

Steel-Dickie mice

(Sl/Sld). A spontaneous mouse mutant with a defect in the production of membrane-bound stem-cell factor (SCF), although secreted SCF is produced normally

BrdU labelling

Incorporation of bromodeoxyuridine (BrdU) into newly synthesized DNA permits indirect detection of proliferating cells using fluorescently labelled BrdU-specific antibodies by either flow cytometry or fluorescence microscopy.

Trabecular bone

Also known as cancellous bone, this is found in areas of rapid turnover such as the ends of the long bones.

Myeloablative agents

Used to completely or partially eliminate the haematopoietic system. These agents include the use of whole-body irradiation or cytotoxic drugs such as 5-fluorouracil.

Osteoblasts

Mesenchymal cells that produce bone matrix that forms bone after mineralization.

Osteoclasts

Large, multi-nucleated cells derived from macrophages that resorb bone. The activity of osteoblasts and osteoclasts form an equilibrium that maintains bone during homeostasis and remodelling.

Endosteum

The cellular lining separating bone from bone marrow. It comprises different cell types including osteoblasts, osteoclasts and stromal fibroblasts.

Bone-marrow sinusoids

Low-pressure vascular channels surrounded by a single layer of fenestrated endothelium.

Bone morphogenetic protein

Induces the formation of bone and cartilage, and is a member of the transforming growth factor-β (TGFβ) superfamily.

Stromal fibroblasts

Part of the endosteal lining separating bone and bone marrow.

Mobilization

The efflux of haematopoietic stem cells from the bone marrow into the vasculature in response to bone-marrow stress or injury, or after treatment with cytokines such as granulocyte colony-stimulating factor (G-CSF).

Homing

The specific movement or migration of haematopoietic stem cells through the vasculature to the bone marrow.

Engraftment

The production of more haematopoietic stem cells by symmetrical divisions and production of a large number of progenitors and differentiated cell types.

LRC assay

(Label retaining cell assay). Identifies long-lived quiescent cells such as adult stem cells. They can be visualized in situ by pulse labelling of their DNA with BrdU (or 3H-thymidine or a histone H2B–EGFP transgene) followed by a chase period of a month or more. Detection of BrdU+ cells requires fixation, precluding subsequent functional analysis.

Angiogenic factors

These factors (which include angiopoietin-1) promote the development of blood vessels, and are particularly important in embryonic and fetal development.

OP9 stromal cells

A bone-marrow-derived cell line that can support the expansion of haematopoietic-cell lineages in culture.

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Wilson, A., Trumpp, A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 6, 93–106 (2006). https://doi.org/10.1038/nri1779

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