The stem cell niches in bone

Abstract

The stem cell niche is composed of a specialized population of cells that plays an essential role in regulating adult stem cell self-renewal and differentiation. In adults, osteoblasts, responsible for osteogenesis, and hematopoietic cells, responsible for hematopoiesis, are closely associated in the bone marrow, suggesting a reciprocal relationship between the two. It was recently discovered that a subset of osteoblasts functions as a key component of the HSC niche (namely, the osteoblastic niche), controlling HSC numbers. HSCs interact not only with osteoblasts but also with other stromal cells, including endothelial cells. Sinusoidal endothelial cells in bone marrow have been revealed as an alternative HSC niche called the vascular niche. In this Review we compare the architecture of these 2 HSC niches in bone marrow. We also highlight the function of osteoblasts in maintaining a quiescent HSC microenvironment and the likely role of the vascular niche in regulating stem cell proliferation, differentiation, and mobilization. In addition, we focus on studies of animal models and in vitro assays that have provided direct insights into the actions of these osteoblastic and vascular niches, revealing central roles for numerous signaling and adhesion molecules. Many of the discoveries described herein may contribute to future clinical treatments for hematopoietic and bone-related disorders, including cancer.

Figure 1. Hematopoiesis of bone cells and marrow stromal cells.

In the bone marrow HSCs reside either next to osteoblasts on the endosteal niche or adjacent to endothelial cells of sinusoidal vessels. Upon each division, 1 daughter cell leaves the bone to proliferate and differentiate into various lineages. HSCs and their progeny are surrounded by stromal cells derived from MSCs, which also reside in the bone cavity. MSCs give rise to chondrocytes, osteoblasts, fibroblasts, adipocytes, endothelium, and myocytes. Osteoblasts (expressing M-CSF, RANKL, and OPG and producing IL-7) may regulate lymphoid (expressing IL-7R) and osteoclast (derived from monocytes, expressing the M-CSF ligand c-Fms and RANK) cell development. CMP, common myeloid progenitor; CLP, common lymphoid progenitor; GMP, granulocyte/macrophage progenitor; MKEP, megakaryocyte erythroid progenitor; MPP, multipotent progenitor stem cell; OC, osteoclast progenitor; SNO cell, spindle-shaped N-cadherin⁺CD45^– osteoblastic cell; TBA, trabecular bone area.

Figure 2. The osteoblastic and vascular niches in bone.

Under normal physiological conditions, HSCs reside in either the osteoblastic or vascular niche. A portion of HSC daughter cells, in response to changes in levels of SDF-1 in the BM, will leave the niche and begin to mobilize and circulate. HSC homing is the reverse of mobilization, occurring in response to higher levels of SDF-1 in the BM. The osteoblastic niche may provide a quiescent microenvironment for HSC maintenance. In contrast, the vascular niche facilitates HSC transendothelial migration during mobilization or homing and may favor HSC proliferation and further differentiation. The process of recruiting HPCs to the vascular niche may depend on endothelium-derived FGF-4 and SDF-1. Higher FGF-4 and oxygen concentration gradients as the cells progress from the osteoblastic niche to the vascular niche might play a role in recruitment, proliferation, and differentiation of HSCs/HPCs. Under stress such as thrombocytopenia, SDF-1 and VEGF activate MMP-9, which converts membrane-associated Kit ligand into soluble Kit ligand (sKitL) and in turn promotes HSCs entry into the cell cycle, mobilization to the vascular niche, and differentiation (34).