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Dynamic niches in the origination and differentiation of haematopoietic stem cells

Nature Reviews Molecular Cell Biology volume 12, pages 643–655 (2011)Cite this article

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A Corrigendum to this article was published on 07 December 2011

This article has been updated

Key Points

  • Haematopoietic stem cells (HSCs) are maintained in specialized microenvironments known as 'niches', which are composed of complex cellular and acellular components. Recent advances have contributed significantly to our understanding of what the niche is and how it changes during development, ageing and disease.

  • In particular, powerful new imaging techniques permit the direct observation of HSCs in their niches. These techniques provide novel insights concerning the emergence of HSCs from the dorsal aorta in fetal haematopoiesis, as well as the associations between HSCs and niche components in adult haematopoiesis.

  • Previous conceptions of niches as static, anatomically-defined bone marrow microenvironments consisting predominantly of one cell type are being challenged. Increasingly, it is becoming clear that the niche is an anatomically fluid and very dynamic environment, wherein multiple physical and cellular inputs are integrated by HSCs.

  • Physical inputs that are known to be important in haematopoiesis include oxygen tension, calcium concentration, shear force and mechanical support. Identified bone marrow niche cells include osteoblasts, vascular endothelial cells, mesenchymal stem cells, CXCL12-abundant reticular cells, neural cells and adipocytes.

  • Recent work demonstrates that dysfunctional haematopoiesis, such as that seen in patients with myelodysplasia and leukaemia, can result from defects in the microenvironment alone, without genetic perturbation of HSCs. This indicates that strategies for correcting haematopoietic diseases that _target only the HSC may be insufficient or incomplete.

  • Many current clinical trials are exploiting our expanding knowledge of niche biology to improve haematopoietic stem cell transplantation. At present, such studies are largely restricted to _targeting relevant niche pathways to effect HSC expansion ex vivo before transplantation; however, future clinical trials will be likely to allow more-directed manipulation of haematopoiesis in vivo.

Abstract

Haematopoietic stem cells (HSCs) are multipotent, self-renewing progenitors that generate all mature blood cells. HSC function is tightly controlled to maintain haematopoietic homeostasis, and this regulation relies on specialized cells and factors that constitute the haematopoietic 'niche', or microenvironment. Recent discoveries, aided in part by technological advances in in vivo imaging, have engendered a new appreciation for the dynamic nature of the niche, identifying novel cellular and acellular niche components and uncovering fluctuations in the relative importance of these components over time. These new insights significantly improve our understanding of haematopoiesis and raise fundamental questions about what truly constitutes a stem cell niche.

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Figure 1: Hierarchical model of haematopoiesis in the adult bone marrow.
Figure 2: Components of a hypothetical HSC 'niche'.
Figure 3: Timeline of haematopoietic development in mice and humans.
Figure 4: Definitive fetal haematopoiesis in the AGM.
Figure 5: Stromal cells in the bone marrow 'niche'.

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Change history

  • 07 December 2011

    The authors wish to correct two typographical errors in the above article. On page 654, there was an error in the highlighted reference comment. The text "References 74-76 and 103 use groundbreaking imaging technology to visualize HSCs in the niche in mice. The authors of references 74, 75 and 103 image murine bones ex vivo, and the authors of references 75 and 76 image cells in the bone in vivo." should have read "References 74-76 and 103 use groundbreaking imaging technology to visualize HSCs in the niche in mice. The authors of references 74 and 103 image bones ex vivo, and the authors of references 75 and 76 image cells in the bone in vivo." Also, on page 650, 'TPO' should have been 'THPO' in figure 5 and 'TPO, thyroid peroxidase' should have read 'THPO, thrombopoietin' in the legend. The Online version has been corrected, and the authors regret any confusion caused to the readers.

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Acknowledgements

We thank L. Silberstein and T. Reya for provision of unpublished data and C. Dall'Osso, A. Hartigan and T. Nageswara Rao for helpful comments on the manuscript. This work was funded, in part, by grants from the US National Institutes of Health (NIH) (HL088582 and HL100402 to A.J.W.) and the Keck Foundation. L.D.W. is supported by an NIH T32 Training Grant (T32CA136432). Content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies.

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Authors and Affiliations

  1. Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, 7 Divinity Ave., Cambridge, 02138, Massachusetts, USA

    Leo D. Wang & Amy J. Wagers

  2. Joslin Diabetes Center, One Joslin Place, Boston, 02215, Massachusetts, USA

    Leo D. Wang & Amy J. Wagers

  3. Dana-Farber/Children's Hospital Cancer Center, Boston, 02215, Massachusetts, USA

    Leo D. Wang

  4. Howard Hughes Medical Institute,

    Amy J. Wagers

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Glossary

Aorta–gonad–mesonephros

(AGM). A region of embryonic mesoderm that develops from the para-aortic splanchnopleura during embryogenesis and gives rise to definitive haematopoietic stem cells.

Myelodysplasia

General term for haematologic defects involving deficiencies in the myeloid blood lineages, which in fact manifest dysfunction in multiple blood lineages. Myelodysplasias are sometimes referred to as 'preleukaemias' because they can transform over time.

Extramedullary

'Outside the marrow.' Used to describe blood formation occurring in anatomical locations that are distinct from the bone marrow. In adults, extramedullary haematopoiesis often signifies haematopoietic stress.

Haemogenic endothelium

A layer of committed endothelial cells that have the capacity to differentiate into blood cells, losing endothelial characteristics and adopting haematopoietic features.

Haemangioblast

An undifferentiated precursor cell formed during development that has the potential to give rise (at the single cell level) to blood cells and endothelial cells, but not to other cell lineages.

Long-term HSCs

(Long-term haematopoietic stem cells; LT-HSCs). Cells that are capable of nearly indefinite self-renewal and differentiation into the mature cells of blood lineages (as assayed by transplantation). These are the bona fide stem cells of haematopoiesis. They are operationally distinct from short-term HSCs, which are capable of only limited self-renewal (but competent to differentiate into the mature cells of all blood lineages) and therefore cannot reconstitute haematopoiesis for the life of an organism.

Cancellous bone

(Also known as trabecular bone). The spongy osseous tissue located at the ends of long bones and within vertebral bodies. It contains haematopoietic (red) marrow but, unlike the medullary cavity of the long bones, also contains trabeculae (tiny osseous beams that traverse the cancellous bone, creating an anatomical and functional structure through which blood and bone marrow elements transit).

Homing

The process whereby haematopoietic stem cells (HSCs) find their way from the circulation to the haematopoietic 'niche'. It is distinct from lodgement, which is the ability of HSCs to enter into 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 lodged.

Endosteal structures

Elements of the endosteum, which is a connective-tissue membrane that lines the inner surface of the medullary (marrow) cavity of the bone. Many researchers also refer to the endosteum as the inner surfaces of the bone (that is, the location of osteoblasts; see the glossary entry for osteoid cells).

Osteoid cells

Cells of the bone lineage: osteocytes, osteoblasts and their precursors. Osteoclasts are not osteoid cells, as they are haematopoietic in origin. Anatomically, osteoid is the unmineralized immature bone matrix laid down by osteoblasts and containing osteocytes.

CXCL12-abundant reticular cells

(CAR cells). Cells that were originally identified on the basis of their high expression of CXC chemokine ligand 12 (CXCL12). CAR cells can be perivascular or endosteal in location.

Vascular sinusoid

A fenestrated capillary-sized blood vessel. Sinusoids are quite porous, permitting the free passage of many blood components.

Parabiosis

A surgical procedure whereby the circulatory systems of two animals are joined such that there is free flow of blood between them.

Non-homologous end joining

A double-strand DNA break repair mechanism that does not make use of a homologous DNA template and is therefore more error-prone than homologous recombination.

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Wang, L., Wagers, A. Dynamic niches in the origination and differentiation of haematopoietic stem cells. Nat Rev Mol Cell Biol 12, 643–655 (2011). https://doi.org/10.1038/nrm3184

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