Molecular Mechanisms of HSC Homing

Since it was first implicated as the major HSC-attracting chemokine (Wright et al. 2002), the CXCL12 (SDF-1) ligand and corresponding CXCR4 receptor have emerged as having the most pivotal role in HSC homing and engraftment yet to be realized. This ligand-receptor pair appears to have some influence at virtually every stage of homing and engraftment (Papayannopoulou 2003, Lapidot et al. 2005, Dar et al. 2006). Briefly, it appears that a chemo-attractive gradient of CXCL12 from the peripheral blood to the bone marrow favors localization of HSCs to the bone marrow (Kim and Broxmeyer 1998), adherence to the bone marrow endothelium, extravasation, and lodgment within bone marrow niches. In addition, a host of molecules thought to have a unique role in HSC migration has recently been shown to influence migration, at least in part, by modulating some aspect of the CXCL12/CXCR4

signaling pathway (Peled A et al. 2000, Papayannopoulou et al. 2001, Nilsson et al. 2002, Avigdor A et al. 2004). Upon successful arrival of a stem cell into the extravascular bone marrow microenvironment, the task of finding a niche remains. In addition to the previously mentioned role of CXCL12 in attracting HSCs to the bone marrow, a gradient of CXCL12 might promote migration to or between niches (Dar et al. 2006, Sugiyama et al. 2006). Other molecules have emerged as regulators of HSC trafficking on the basis of their interaction with CXCL12 or CXCR4, for example, the sphingosine 1-phosphate receptor agonist FTY720 (Kimura T et al. 2004) and the well-known CXCR4 receptor antagonist AMD3100 (Vartanian 2000). Other novel modulators of the CXCL12/CXCR4 axis include extracellular UTP (Rossi L et al. 2007b) and the third complement component (C3) (Ratajczak et al. 2006).

Unlike the diverse functions of CXCL12 and CXCR4, E- and P- selectins appear to act more specifically to facilitate HSC homing by promoting the rolling of HSCs on endothelial cells of the bone marrow vasculature (Frenette et al. 1998, Mazo et al. 1998). The integrins very late activation antigen-4/vascular cell adhesion molecule-1(VLA-4/VCAM-1) and lymphocyte function associated anti-gen-1 (LFA-1) are thought to have similar functions, as well as the ability to promote the actual transendothelial migration/extravasation of HSCs (Peled A et al. 2000; Papayannopoulou et al. 2001).

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