Figure 1.

The cellular components of the BM niches include endothelial cells, HSCs, megakaryocytes, osteoblasts, osteoclasts, adipocytes, sympathetic neurons that are related to Schwann’s cells, bone macrophages and reticular cells (90, 92). Both soluble factors and direct contact between cells regulate HSC maintenance. Quiescent HSCs are kept in contact with osteoblasts and Nestin+ MSCs as well as CXCL12 - abundant reticular (CAR) cells in the perivascular niche; both secrete soluble factors such as Stem Cell Factor (SCF), CXCL12 (CXC motif chemokine ligand 12) and Ang-1 (Angiopoietin-1) while in the perivascular niche, secrete (93). Osteomacs, the bone-marrow-resident macrophages are also found in the endosteal niche and facilitate colonization; in the absence of osteomacs, HSCs are shown to leave BM and join circulation (92, 94). Jagged-1 is released from cells of osteocyte lineage, and responsible for the activation of Notch pathway (95). Organized as a monolayer in the internal compartment of blood vessels, ECs take part in various physiological processes including facilitating blood flow, contributing coagulation, nutrient exchange and regulate hematopoiesis (96). According to their localization in the BM, they are divided into two categories: sinusoid endothelial cells (SECs) which have low CD31 and Endomucin expression (type L), or arteriolar endothelial cells (AECs) with CD31 and Endomucin expression (type H). Both cell types play different roles in the modulation of BM niche (97). SECs are the compartments of more permeable sinusoidal vessels and secrete high levels of CXCL12 as well as E-selectin that regulate HSC homing (96, 98). On the contrary, AECs are the compartments of arteriolar vessels which have low penetration and ensure a relatively hypoxic environment (99, 100). AECs generate SCF which play a fundamental role in maintaining HSCs and express CXCL12. In addition, they produce Netrin-1 that retains HSCs’ quiescence and self-renewal (101). Megakaryocytes are the basic subunit in the perisinusoidal area and regulate HSC quiescence (102–104). In the endosteal niche, osteoblasts stabilize bone formation and produce mediators which are essential for HSC maintenance; and CXCL12, granulocyte colony-stimulating factor (G-CSF), SCF, Annexin 2 (ANXA2), Ang-1, Thrombopoietin (TPO) that are required for the regulation of HSC homing, quiescence and mobilization (105–113). Schwann cells are found in the perivascular niche and protect the quiescent HSCs through transforming growth factor-β (TGF-β) (114). Bone marrow adipocytes were also reported to support HSC proliferation through secreting adiponectin and contribute to energy metabolism (115, 116).