Multiple signaling and adhesion molecules are involved in stem cell–niche interactions, contributing diverse characteristics to each niche’s function. Well-studied signaling molecules involved in niche regulation include SCF/c-Kit, Jagged/Notch, angiopoietin-1/Tie2 (Ang-1/Tie2), and Ca2+
-sensing receptor (CaR) (28
). This section will cover these as well as other molecules, including Wnt, BMP, TPO, IL-3, and IL-6, known to play roles in stem cell regulation. It is presently unclear whether all of the latter molecules are present in the niches.
SCF signaling through its receptor, c-Kit, has been well characterized in promoting both proliferation and survival of HSCs. Loss of SCF from supporting cells in sl/sl
mice, or loss of the receptor in HSCs in W/W
mice, leads to hematopoietic failure, indicating essential roles for these molecules in niche function (57
). These results are supported by more recent work revealing a direct role for SCF/c-Kit signaling in control of HSC activation and release from the niche (28
Notch is expressed in primitive HSCs, while the Notch ligand Jag1 is expressed by mouse osteoblasts and bone marrow stromal cells. Activation of the PPR can increase osteoblastic cell numbers concomitant with enhanced Jag1/Notch activity, resulting in expansion of the HSC population (32
). This observation is consistent with previous reports that activation of Notch signaling is able to maintain undifferentiated stem and progenitor cells and expand the HSC/HPC pools (58
Ang-1 is expressed in osteoblasts, while Tie2, a tyrosine kinase receptor, is expressed in HSCs and endothelial cells. Ang-1 enhances the ability of HSCs to become quiescent and can induce adhesion to osteoblastic cells through Tie2 (33
Recently, CaR was found to facilitate retention of HSCs on the endosteal bone surface. Deficiency of CaR in knockout mice leads to release of HSCs into the bloodstream. Interestingly, although CaR deficiency permitted HSC homing to BM in these animals, the cells were unable to remain localized to the osteoblastic niche (55
BMP and Wnt signaling pathways are also involved in stem cell regulation. BMP-4 is expressed in osteoblastic cells (J. Zhang and L. Li, unpublished observations), but the type of BMP receptor expressed in HSCs is unknown (12
). Wnt signals are important for stem cell self-renewal (60
), but the identity of the niche (osteoblastic or vascular) that expresses any of numerous canonical and noncanonical Wnt molecules is unknown. The same is true for FGF and hedgehog, both of which affect HSC behavior in vitro (62
). However, whether and where these factors are present as niche signals remain unresolved. In addition, well-documented studies have shown that IL-3 or IL-6 combined with TPO signaling can influence stem cell proliferation and differentiation (64
). However, details regarding whether they are present specifically within the osteoblastic or vascular niches are unknown.