The bone marrow at the crossroads of blood and immunity

Subjects

Key Points

  • Bone marrow cellular niches are functional compartments that regulate haematopoietic stem cell (HSC) and immune cell behaviour through direct cell contact, growth factors and cytokines, and components of the extracellular matrix.

  • Within the bone marrow, HSCs are regulated by components of the vasculature, the trabecular bone and the surrounding stroma.

  • In addition to its role as a primary lymphoid organ through the support of lymphoid development, the bone marrow can act as a host for naive and memory immune cells, plasma cells, regulatory T cells and myeloid immune cells.

  • The bone marrow is heterogeneous with regard to perfusion, oxygenation and innervation. Together, studies exploring these features allow us to consider new ways in which the bone marrow cellular niches are constituted and regulated.

  • Because the haematopoietic and immune systems need to rapidly respond and adapt to the needs of the organism, their niches should not be viewed as static entities. For example, these niches can respond to particular states of injury and inflammation.

  • A better understanding of the dynamic interactions between HSCs, immune cells and their niches could yield significant therapeutic benefit in contexts such as chemotherapy, radiation injury or invasion of the niche by malignancies.

Abstract

Progenitor cells that are the basis for all blood cell production share the bone marrow with more mature elements of the adaptive immune system. Specialized niches within the bone marrow guide and, at times, constrain the development of haematopoietic stem and progenitor cells (HSPCs) and lineage-restricted immune progenitor cells. Specific niche components are organized into distinct domains to create a diversified landscape in which specialized cell differentiation or population expansion programmes proceed. Local cues that reflect the tissue and organismal state affect cellular interactions to alter the production of a range of cell types. Here, we review the organization of regulatory elements in the bone marrow and discuss how these elements provide a dynamic means for the host to modulate stem cell and adaptive immune cell responses to physiological challenges.

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Figure 1: Haematopoietic stem cell niches.
Figure 2: Immune cell niches.
Figure 3: Functional organization of the bone marrow.
Figure 4: Possible mechanisms by which bone marrow niches adapt to changes.

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Acknowledgements

The authors would like to thank D. B. Sykes, L. Silberstein and I. Droujinine for their comments on the manuscript. Thanks also go to J.-P. Lévesque and S. Méndez-Ferrer for generously contributing to Fig. 3. F.E.M. is a recipient of a Clinician Scientist Training Award from the Canadian Institutes of Health Research. C.R. was funded by Massachusetts General Hospital institutional funds. This work was supported by the Ellison Medical Foundation and the National Heart, Lung and Blood Institute (grants U01HL10042 and R01HL44851).

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Correspondence to David T. Scadden.

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David T. Scadden is a shareholder in Fate Therapeutics and a consultant to Genzyme, Hospira and Fate Therapeutics.

Francois E. Mercier and Christine Ragu have no competing financial interests.

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Adventitial cells

Connective tissue cells that surround small blood vessels and have a supportive structural role and possibly other functions, such as blood flow regulation.

Trabecular bone

A network of bony projections that is present at the ends of long bones and forms a highly vascularized, porous matrix that is the main site of haematopoiesis in adults.

Osterix

(Also known as SP7). A zinc finger-containing transcription factor that is required for the commitment of mesenchymal cells to the osteoblastic lineage.

Dicer1

This gene encodesDicer, an endoribonuclease that cleaves double-stranded RNA and is important for processing pre-microRNAs.

Epigenetic changes

Modifications in the activation state of certain genes that persist following cell division. These alterations are not related to changes in DNA sequence, but are induced through other mechanisms, such as DNA methylation and histone modifications.

T cell-independent antigens

Antigens that do not require T cell help to induce specific antibody production. These antigens are commonly polymeric antigens, such as polysaccharides and lipids.

Splenic marginal zone

An area in the spleen with the major function of trapping circulating antigens. The marginal zone is populated by a distinct population of lymphocytes that can be readily activated following exposure to blood-borne pathogens.

CD34+CD38 progenitor cells

A population of cells within the human haematopoietic system that is defined by the expression of cell-surface markers and is enriched in stem cells and progenitors.

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Mercier, F., Ragu, C. & Scadden, D. The bone marrow at the crossroads of blood and immunity. Nat Rev Immunol 12, 49–60 (2012). https://doi.org/10.1038/nri3132

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