Diversity in the bone marrow niche: Classic and novel strategies to uncover niche composition

Abstract

Our view on the role and composition of the bone marrow (BM) has dramatically changed over time from a simple nutrient for the bone to a highly complex multicellular tissue that sustains haematopoiesis. Among these cells, multipotent haematopoietic stem cells (HSCs), which are predominantly quiescent, possess unique self-renewal capacity and multilineage differentiation potential and replenish all blood lineages to maintain lifelong haematopoiesis. Adult HSCs reside in specialised BM niches, which support their functions. Much effort has been put into deciphering HSC niches due to their potential clinical relevance. Multiple cell types have been implicated as HSC-niche components including sinusoidal endothelium, perivascular stromal cells, macrophages, megakaryocytes, osteoblasts and sympathetic nerves. In this review we provide a historical perspective on how technical advances, from genetic mouse models to imaging and high-throughput sequencing techniques, are unveiling the plethora of molecular cues and cellular components that shape the niche and regulate HSC functions.

Keywords: bone marrow niche; cellular interactomes; haematopoietic stem cells; murine models; single-cell technologies.

FIGURE 1

Schematic of the bone marrow (BM) microenvironment and its main regulatory components. The highly specialised BM niche supports and regulates the functions and dynamics of haematopoietic stem cells (HSCs) and other haematopoietic progenitors. Cumulative research indicates that arterioles, sinusoids and associated perivascular stromal cells play a key role in HSC maintenance. Besides endothelial cells, which produce stem cell factor (SCF) and CXC‐chemokine ligand 12 (CXCL12), vascular niche components include mesenchymal stem cells (MSCs) such as periarteriolar NG2⁺ cells, Nestin^high cells, MYH11⁺ cells, CXCL12‐abundant reticular (CAR) cells, perisinusoidal LepR⁺ cells and Nestin^low cells. Of note, there is a significant overlap between these MSCs populations. Recently described Osteo‐CAR and adipo‐CAR cells produce the highest cytokine levels in the BM and preferentially localise close to arteriolar and sinusoidal niches, respectively. Sympathetic nerves, through the release of noradrenaline (NA), are also important regulators of the HSC niche. Non‐myelinating Schwann cells produce transforming growth factor β (TGFβ) controlling HSC quiescence. The role of osteoblasts in HSC regulation is controversial but they may regulate lymphoid progenitors. Macrophages and megakaryocytes are mature haematopoietic cell types that control HSC behaviour via the release of TGFβ and CXCL4 respectively. Further studies are required to elucidate the role of adipocytes. Imaging studies of HSC subsets have demonstrated the existence of different bone marrow niches for platelet‐myeloid‐biased von Willebrand factor (VWF ⁺ HSCs and lymphoid biased (VWF ⁻) HSCs. In the figure, the endosteal and vascular niches (arteriolar and sinusoidal) are highlighted by changes in the colour of the background. For simplicity, only relevant HSC niche components are shown. Other structural components as different fibroblast‐like cells with unknown roles as HSC niche components are not included.