The bone marrow at the crossroads of blood and immunity

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.

Figure 1. Haematopoietic stem cell niches

In the bone marrow, haematopoietic stem cells (HSCs) can be found near the endosteal surface (a); in association with CXCL12-abundant reticular (CAR) cells (b); and in the periphery of sinusoids and perivascular nestin-expressing cells (c). Each niche is thought to provide signals that support HSC behaviour, although the relationship between HSCs that are present in different niches is still unclear (dotted arrows). Likewise, blood vessels in the bone marrow are often in close association with bone, although their interaction is still poorly understood (d). At the endosteal surface, osteoblastic cells express factors that participate in HSC retention; osteoclasts regulate osteoblastic cell function by inducing bone remodelling; and macrophages regulate osteoblastic cell activity and the retention of HSCs. In the bone marrow stroma, HSCs are associated with CAR cells, which express factors that promote HSC retention. Adipocytes negatively regulate HSCs in the steady state. In the perivascular area, HSCs are associated with nestin-expressing cells, which promote HSC retention and are regulated by macrophages and the sympathetic nervous system (SNS).

Figure 2. Immune cell niches

During B cell differentiation, haematopoietic stem cells (HSCs) and pre-pro-B cells are found in close association with CXCL12-abundant reticular (CAR) cells (a), whereas pro-B cells are more often in contact with interleukin-7 (IL-7)-secreting stromal cells (b). Later in B cell development, a population of immature B cells can be found in close association with endothelial cells (c). Naive B and T cells, which can respond to blood-borne pathogens, are found within a perivascular niche that is constituted by a network of dendritic cells (DCs) (d). Bone marrow-resident memory CD4⁺ T cells reside next to IL-7-secreting stromal cells and are mostly found in a quiescent state (_e). Plasma cells also reside in the bone marrow. CAR cells, eosinophils and megakaryocytes express factors that promote plasma cell engraftment and survival (f).

Figure 3. Functional organization of the bone marrow

The three panels show representative images obtained using techniques that can be applied to study perfusion, oxygenation and innervation of the bone marrow compartment and to highlight its heterogeneity. a | Study of the perfusion state of nucleated cells in the mouse bone marrow. Bone marrow was harvested 10 minutes after intravenous administration of Hoechst 33342 dye and fluorescence intensity was measured by flow cytometry. Different populations are defined according to the percentile of fluorescence intensity and can later be studied by immunophenotype or functional assays. b | Study of the oxygenation state in the mouse bone marrow. Hypoxic regions within femur sections were stained using pimonidazole and imaged 3 hours after intravenous pimonidazole injection. Pimonidazole is identified by a fluorescein isothiocyanate (FITC)-labelled pimonidazole-specific monoclonal IgG1 antibody (green), and the nuclei are visualized using 4′,6-diamidino-2-phenylindole (DAPI) staining (blue). Images were acquired by confocal laser scanning microscopy using an X10 objective. The staining is heterogeneous and present both at the endosteal surface and at other locations, but the image is two-dimensional and therefore anatomical relationships are of limited precision. c | Study of the innervation of the mouse bone marrow. Whole-mount staining of the skull bone marrow revealed subendothelial nestin-expressing mesenchymal stromal cells that are innervated by sympathetic fibres. The projection stack (of depth ~100 μm) of fluorescent images shows the distribution of cells that express a nestin–GFP (green fluorescent protein) conjugate (green), as well as that of vascular endothelial cells that express CD31 (also known as PECAM1) (blue) and of sympathetic nerve fibres that express tyrosine hydroxylase (red).

Figure 4. Possible mechanisms by which bone marrow niches adapt to changes

a | The bone marrow cellular pool is divided between different populations of mature and immature cells. We propose here that mature cell types provide negative feedback to limit progenitor numbers through the secretion of negative regulators or by competing with variable efficiency for niche factors. b | Loss of inhibition by the dominant cell type allows the expansion of the progenitor populations. c | Alternatively, extrinsic factors that modify the composition of the niche alter the balance of the different populations.