Multiple signaling and adhesion molecules are involved in stemcell–niche interactions, contributing diverse characteristicsto each niche’s function. Well-studied signaling moleculesinvolved in niche regulation include SCF/c-Kit, Jagged/Notch,angiopoietin-1/Tie2 (Ang-1/Tie2), and Ca2+-sensing receptor(CaR) (28, 32, 33, 55, 56). This section will cover these aswell as other molecules, including Wnt, BMP, TPO, IL-3, andIL-6, known to play roles in stem cell regulation. It is presentlyunclear whether all of the latter molecules are present in theniches.
SCF signaling through its receptor, c-Kit, has been well characterizedin promoting both proliferation and survival of HSCs. Loss ofSCF from supporting cells in sl/sl mice, or loss of the receptorin HSCs in W/W mice, leads to hematopoietic failure, indicatingessential roles for these molecules in niche function (57).These results are supported by more recent work revealing adirect role for SCF/c-Kit signaling in control of HSC activationand release from the niche (28).
Notch is expressed in primitive HSCs, while the Notch ligandJag1 is expressed by mouse osteoblasts and bone marrow stromalcells. Activation of the PPR can increase osteoblastic cellnumbers concomitant with enhanced Jag1/Notch activity, resultingin expansion of the HSC population (32). This observation isconsistent with previous reports that activation of Notch signalingis able to maintain undifferentiated stem and progenitor cellsand expand the HSC/HPC pools (58, 59).
Ang-1 is expressed in osteoblasts, while Tie2, a tyrosine kinasereceptor, is expressed in HSCs and endothelial cells. Ang-1enhances the ability of HSCs to become quiescent and can induceadhesion to osteoblastic cells through Tie2 (33).
Recently, CaR was found to facilitate retention of HSCs on theendosteal bone surface. Deficiency of CaR in knockout mice leadsto release of HSCs into the bloodstream. Interestingly, althoughCaR deficiency permitted HSC homing to BM in these animals,the cells were unable to remain localized to the osteoblasticniche (55).
BMP and Wnt signaling pathways are also involved in stem cellregulation. BMP-4 is expressed in osteoblastic cells (J. Zhangand L. Li, unpublished observations), but the type of BMP receptorexpressed in HSCs is unknown (12). Wnt signals are importantfor stem cell self-renewal (60, 61), but the identity of theniche (osteoblastic or vascular) that expresses any of numerouscanonical and noncanonical Wnt molecules is unknown. The sameis true for FGF and hedgehog, both of which affect HSC behaviorin vitro (62, 63). However, whether and where these factorsare present as niche signals remain unresolved. In addition,well-documented studies have shown that IL-3 or IL-6 combinedwith TPO signaling can influence stem cell proliferation anddifferentiation (64, 65). However, details regarding whetherthey are present specifically within the osteoblastic or vascularniches are unknown.
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