The physiological role of CXCR7 in adult tissues remains unclear. Dispute concerning direct signaling and typical chemokine responses after SDF-1 and I-TAC binding to CXCR7, including calcium flux and kinase phosphorylation leading to motility and chemotaxis, has yet to be settled. Furthermore, all these CXCR7-dependent signaling responses may vary with cell type.
The best and well-studied normal cell model so far are lymphocytes. However, reported data are contradictory. In an initial report, CXCR7 was described as a receptor that enhances SDF-1-dependent chemotaxis of human T lymphocytes together with CXCR4 (Balabanian et al., 2005
). The chemotactic response of these cells to SDF-1 gradient was decreased if anti-CXCR7 antibodies blocked CXCR7. In the same study, it was also shown that T lymphocytes highly express CXCR7, which could be internalized after SDF-1 binding (Balabanian et al., 2005
). Nevertheless, no data showing activation of intracellular signaling pathways were demonstrated at that point. In another study, these observations were not confirmed. First, CXCR7 was found to be expressed at very low levels on human T lymphocytes and no chemotactic responses of T lymphocytes or activation of MAPKp42/44 and Akt pathways were observed after CXCR7 activation by SDF-1 and/or I-TAC (Hartman et al., 2008
). Different level of CXCR7 expression was reported by both groups. However, it could be explained by cells being fixed before staining in the first study, which also allowed the detection of intracellular CXCR7 (Hartman et al., 2008). In agreement with this notion and as mentioned above, CXCR7 was found to be mainly expressed intracellularly in lymphocytic cells, being enriched in the so-called sub-membrane area containing early endosomes that is accessible for antibodies after cellular permeabilization (Hartman et al., 2008). This was confirmed by showing co-localization of CXCR7 with the early endosomal marker EEA1 (Hartman et al., 2008). The intracellular localization of CXCR7 may at least account for differences in reported CXCR7 surface expression studies. However, discrepancies for functional chemotaxis data between both reports are not clear at this point.
In addition to T-lymphocytes, it was postulated that CXCR7 may play a role in B lymphopoiesis (Infantino et al., 2006
). Accordingly, CXCR7, similarly to CXCR4, was found to be expressed by normal B lymphocytes and its expression seems to be tightly regulated during B-cell development and differentiation (Infantino et al., 2006
). In addition, since CXCR7 expression in blood-derived switch memory B-cells correlates with differentiation of these cells after activation into immunoglobulin producing plasma cells, CXCR7 could be a marker for memory B-cells, which are precursors of antibody producing cells. Moreover, it was postulated that activated mature plasmocytoid dendritic cells produce unknown ligand for CXCR7 that could selectively downregulate expression of CXCR7 (Infantino et al., 2006
). Again, no convincing signaling data in B-lymphocytes are presented so far to confirm these observations. Of note, despite CXCR7 being implicated in lymphopoiesis, no major developmental defects in lymphoid tissues were reported in CXCR7 KD animals (Sierro et al., 2007
). This suggests that these effects, if present, could be rather subtle in nature.
An open question remains of whether CXCR7 is playing any role in homing, mobilization, proliferation, and survival of stem cells similarly to CXCR4. Lack of major hematopoietic defects in CXCR7 KD mice argues against this possibility. In addition, CXCR7 seems to be expressed at very low levels on CD34+ cells (Hartman et al., 2008). As mentioned, its expression and potential biological significance on most primitive hematopoietic stem cells was not reported so far. Thus, a question of the importance of the SDF-1-CXCR7 axis in adult hematopoiesis remains unanswered and could be additionally addressed by appropriate CXCR7 inducible knock-out experiments in hematopoietic cells performed after birth in adult animals.
Interestingly, CXCR7 was found to be expressed together with the CXCR4 on a population of renal progenitor cells in human kidneys endowed with regenerative kidney potential as established in a model of immunodeficient mice (Mazzinghi et al., 2007). Accordingly, blockade of either CXCR7 or CXCR4 abolished SDF-1-mediated engraftment of these cells in vivo in immunodeficient mice with acute renal failure. However, activity of both CXCR4 and CXCR7 was essential for transendothelial migration of renal progenitors. CXCR7 was found to be crucial for adhesion of these cells to endothelium, which is the first step for their migration into injured tissues. Similar pro-survival activity of CXCR7 was postulated for neural cells during ischemia related with stroke (Shonemeier et al., 2008). It is not clear at this point if neural progenitors express CXCR7, in contrast to mature cells in brain, and whether this receptor is functional. These results should also prompt other investigators to examine if CXCR7 is a marker of monopotent stem cells committed for various tissues (e.g., satellite-, oval-, neural-, or cardiac- stem cells) similarly to CXCR4 and whether it functions in the trafficking/circulation and biology of these cells.
CXCR7 may also play a role in homeostasis and pathology of connective tissues. As previously mentioned, CXCR7 is expressed on osteocytes in adult bones and chondrocytes in joints (Jones et al., 2006
). It was reported that stimulation of CXCR7 promotes synthesis of matrix metalloprotease (MMP)-1, MMP-13, and vascular endothelial growth factor (VEGF) and suppresses expression of collagen-2 and matrix synthesis. In addition and concurrently, CXCR7 stimulation up-regulates synthesis of collagen-10, IL-8, osteopontin, and osteocalcin. All this together suggests that CXCR7 may mediate early development of osteoarthritis and endochondrial ossification (Jones et al., 2006
Finally, as discussed previously, in addition to CXCR7 being an SDF-1 sink that decreases local SDF-1 concentration required for proper migration of primordium and lateral line (Boldajipour et al., 2008
), some authors suggest active CXCR7 signaling during primordium migration. Inhibition of CXCR7 expression in zebrafish leads to stretching of the primordium, indicating that primordial migration is regulated by SDF-1 acting through two receptors, i.e., CXCR4 on the leading portion and CXCR7 on the trailing part of the migrating group. Furthermore, it is suggested that proper functioning of the SDF-1-CXCR4 and SDF-1-CXCR7 axes requires the presence of anosmin-1a (Boldajipour et al., 2008
). Since depletion of both anosmin-1a and SDF-1 leads to defects in migration of the posterior lateral line of primordium and its disruption, anosmin-1a may take part in activation of signaling on both SDF-1-activated receptors.