The bone marrow niche for haematopoietic stem cells

Abstract

Niches are local tissue microenvironments that maintain and regulate stem cells. Haematopoiesis provides a model for understanding mammalian stem cells and their niches, but the haematopoietic stem cell (HSC) niche remains incompletely defined and beset by competing models. Recent progress has been made in elucidating the location and cellular components of the HSC niche in the bone marrow. The niche is perivascular, created partly by mesenchymal stromal cells and endothelial cells and often, but not always, located near trabecular bone. Outstanding questions concern the cellular complexity of the niche, the role of the endosteum and functional heterogeneity among perivascular microenvironments.

Figure 1. Bone marrow anatomy

Haematopoietic stem cells (HSCs) reside primarily within bone marrow during adulthood. Bone marrow is a complex organ containing many different haematopoietic and non-haematopoietic cell types. Bone marrow is surrounded by a shell of vascularized and innervated bone. a. Minute projections of bone (trabeculae) are found throughout the metaphysis such that many cells in this region are close to bone surface. b. The interface of bone and bone marrow is known as the endosteum, which is covered by bone-lining cells that include bone-forming osteoblasts and bone-resorbing osteoclasts. Arteries carry oxygen, nutrients, and growth factors into the bone marrow, before feeding into sinusoids, which coalesce as a central sinus to form the venous circulation. Sinusoids are specialized venuoles that form a reticular network of fenestrated vessels that allow cells to pass in and out of circulation. There is a particularly rich supply of arterioles as well as sinusoids near the endosteum. c. 3-D reconstructed photomicrograph from the marrow looking toward the endosteal surface (blue) from 50 μm below the surface, revealing the rich network of vessels (red) (courtesy of Charles Lin, Joel Spencer and Juwell Wu). Smaller arteriolar vessels (white arrows) become larger sinusoidal vessels. The field of view is 350μm × 350μm. d. A cross-sectional view of blood vessels that run along the endosteal surface (ev) and that transition (white arrow) into sinusoids (s) that then course toward the central sinus (from ref). e. The bone marrow is cellularly complex with CD150⁺CD48⁻CD41⁻Lineage⁻ HSCs (arrow) residing in close contact with not only vascular and perivascular cells (*, sinusoid lumens) but also megakaryocytes (large yellow cells) and other haematopoietic cells (image from ref).

Figure 2. HSCs and their niche cells surround sinusoids throughout the bone marrow

a. Sections through the bone marrow of Scf^gfp/+ mice show that HSC niche cells (green) include mesenchymal stromal cells and endothelial cells that surround sinusoids and potentially other blood vessels throughout the bone marrow. b–d. High magnification shows that Scf-GFP overlaps with the endothelial marker endoglin but also extends beyond the endoglin on the abluminal side of the sinusoids, indicating expression by mesenchymal stromal cells. e. Scf-GFP is not expressed by osteopontin+ bone lining cells around trabecular bone, but is expressed by some nearby perivascular cells. f. Cxcl12-DsRed exhibits a similar expression pattern, primarily by perivascular mesenchymal cells and endothelial cells around sinusoids throughout the bone marrow, in a pattern that strongly overlaps with Scf-GFP in Cxcl12^DsRed/+; Scf^gfp/+ mice. g–j, Cells that are CD150+ (g) and CD48 and Lineage marker negative (h) are usually found immediately adjacent to Scf-GFP+ perivascular cells (i) in the bone marrow (see j for merge). Images are from references^,.

Figure 3. HSCs and restricted haematopoietic progenitors occupy distinct niches in the bone marrow

a. HSCs are found mainly adjacent to sinusoids throughout the bone marrow^,,,, where endothelial cells and mesenchymal stromal cells promote HSC maintenance by producing SCF, CXCL12^,,, and likely other factors. Similar cells may also promote HSC maintenance around other types of blood vessels, such as arterioles. The mesenchymal stromal cells can be identified based on their expression of Lepr-Cre, Prx1-Cre, Cxcl12-GFP, or Nestin-GFP transgene in mice and similar cells are likely to be identified by CD146 expression in humans. These perivascular stromal cells, which likely include Cxcl12-abundant Reticular (CAR) cells, are fated to form bone in vivo, express Mx-1-Cre and overlap with CD45/Ter119⁻PDGFRα ⁺Sca-1⁺ stromal cells that are highly enriched for MSCs in culture. b. It is likely that other cells also contribute to this niche, likely including cells near bone surfaces in trabecular rich areas. Other cell types that regulate HSC niches include sympathetic nerves^,, non-myelinating Schwann cells (which are also Nestin+), macrophages, osteoclasts, extracellular matrix ^,, and calcium. Osteoblasts do not directly promote HSC maintenance but do promote the maintenance and perhaps the differentiation of certain lymphoid progenitors by secreting Cxcl12 and likely other factors^,,,. Early lineage committed progenitors thus reside in an endosteal niche that is spatially and cellularly distinct from HSCs.