The bone marrow stem cell niche grows up: mesenchymal stem cells and macrophages move in

Abstract

Stem cell niches are defined as the cellular and molecular microenvironments that regulate stem cell function together with stem cell autonomous mechanisms. This includes control of the balance between quiescence, self-renewal, and differentiation, as well as the engagement of specific programs in response to stress. In mammals, the best understood niche is that harboring bone marrow hematopoietic stem cells (HSCs). Recent studies have expanded the number of cell types contributing to the HSC niche. Perivascular mesenchymal stem cells and macrophages now join the previously identified sinusoidal endothelial cells, sympathetic nerve fibers, and cells of the osteoblastic lineage to form similar, but distinct, niches that harbor dormant and self-renewing HSCs during homeostasis and mediate stem cell mobilization in response to granulocyte colony-stimulating factor.

Figure 1.

Location of HSC niches in trabecular bone cavities. HSCs are located at the endosteum, which is lined by OBs and is remodeled by osteoclasts. OBs promote HSC maintenance. Vascular sinusoids are found close to the endosteum, but more frequently at greater distances. HSCs are also situated nearby sinusoids toward the center of the marrow. Perivascular nestin⁺ MSCs and the more abundant CAR cells promote HSC maintenance.

Figure 2.

Model illustrating the quiescent endosteal and the active perivascular HSC niche during bone marrow homeostasis. Deeply quiescent (dormant) HSCs in the endosteal niche are likely in close contact with OBs and nestin⁺ MSCs, both of which supply HSC maintenance and quiescence factors, including CXCL12, SCF, Ang-1, VCAM-1, and TPO, and cooperate to retain HSCs in their niche. MSCs can generate OBs, adipocytes, and chondrocytes. The perivascular niche is more distant from the endosteum and does not contain OBs, but includes perivascular CAR cells that secrete factors that promote self-renewal of active HSCs, which are significantly more abundant than dormant HSCs. Self-renewal is also stimulated by Notch ligands expressed by sinusoidal endothelial cells. Both niches contain perivascular nestin⁺ MSCs as a key component. Different subtypes of phagocytes support the maintenance of OBs (osteomacs) and maintenance and proliferation of MSCs (macrophages). They also induce the expression of HSC maintenance factors. The SNS inhibits MSC proliferation and induces circadian oscillations of CXCL12 expression. CAMS, cell adhesion molecules.

Figure 3.

Model illustrating the quiescent endosteal niche and the active perivascular HSC niche after stimulation with G-CSF or depletion of monocytes/macrophages. Upon stimulation with G-CSF, which binds G-CSFR on monocytic cells, the monocytes/macrophages disappear. As a consequence of their missing supportive activity, OB activity is decreased and nestin⁺ MSCs no longer express high levels of SCF, VCAM1, Ang-1, and CXCL12. Because CXCL12-mediated activation of the CXCR4 receptor on HSCs is a critical niche retention signal, HSCs get mobilized into the periphery via entry into the sinusoids. Alternatively, the CXCR4/CXCL12 axis can be inhibited by the clinically used mobilizing agent AMD3100. Additionally, G-CSF stimulates the SNS, which contributes to HSC mobilization. CAMS, cell adhesion molecules.