Overall G-protein linked receptor family includes receptors for hormones, cytokines, neurotransmitters, visual light waves, and chemokines (Schier, 2003). Members of this receptor family are seven-transmembrane-spanning proteins residing predominantly in plasma membrane that transduce signals by coupling to guanine nucleotide-binding proteins (G-proteins). G-protein-coupled receptors regulate several aspects of cell biology with chemokine receptors being an important part of this family (Schier, 2003).

Chemokines, the small pro-inflammatory chemoattractant cytokines that bind to specific G-protein-coupled seven-transmembrane receptors present on the plasma membranes of target cells, are the major regulators of cell trafficking and adhesion (Zlotnik and Yoshie, 2000). Some chemokines are also reported to modulate cell survival and growth (Horuk, 2001). More than 50 different chemokines and 20 different chemokine receptors have been cloned so far (Zlotnik and Yoshie, 2000, Horuk, 2001).

Chemokines usually bind to multiple receptors and the same receptor may bind more than one chemokine. However, one exception to this rule was accepted for many years; the α-chemokine stromal-derived factor-1 (SDF-1) or CXCL12 binds exclusively to CXCR4 and has CXCR4 as its only receptor (Nagasawa et al., 1996, Ma et al., 1999, Bagri et al., 2002, Lazarini et al., 2003). This assumption was based on SDF-1 and CXCR4 murine knock-down (KD) data in which affected animals display similar phenotype. The concept that CXCR4 only binds SDF-1 suggested that the SDF-1-CXCR4 axis might play a uniquely important biological role among chemokine-chemokine receptors. This notion was also supported by the murine KD data, which also showed that SDF-1 secreted by bone marrow stromal cells during embryogenesis is critical for the colonization of marrow by fetal liver-derived hematopoietic stem/progenitor cells (David et al., 2002, Lapidot and Petit, 2002, Kortesidis et al., 2005). Furthermore, during adult life, SDF-1 has a pivotal role in the retention and homing of these cells into the bone marrow microenvironment (Aiuti et al., 1997, Kim et al., 1998, Lapidot and Petit, 2002, Guo et al., 2005). Thus, it is not surprising that perturbation of the SDF-1-CXCR4 axis (e.g., as seen after administration of mobilizing agents) is essential for the egress and mobilization of hematopoietic stem/progenitor cells from the bone marrow into peripheral blood (Devine et al., 2004, Lapidot et al., 2005, Papayannopoulou 2004, Pelus et al., 2008). On the other hand, proper functioning of the SDF-1-CXCR4 axis is crucial in directing homing and engraftment of hematopoietic stem cells into bone marrow after transplantation (Lapidot et al. 2005). Furthermore, the SDF-1-CXCR4 axis was also reported to be involved in proper development of brain, particularly the cerebellum (Zou et al.; 1998), as well as the ventricular septum in heart (Tachibana et al., 1998) and gastrointestinal vasculature (Nagasawa, 2001). In addition to hematopoietic stem/progenitor cells, SDF-1 was found to be an important developmental chemoattractant for several other types of organ/tissue-committed stem cells, including a population of pluripotent very small embryonic-like stem cells described by our team (Kucia et al., 2004). In the case of hematopoietic stem/progenitor cells, however, SDF-1 is the most important and pivotal chemoattractant so far (Aiuti et al., 1997, Nagasawa et al., 1996, Kucia et al., 2005).

SDF-1 becomes highly expressed in injured organs (e.g., heart infarct, stroke) and may chemoattract circulating CXCR4⁺ stem cells including very small embryonic like stem cells for tissue repair (Dalakas et al., 2005, Wojakowski et al., 2006, Ratajczak et al., 2006). In addition, mounting evidence suggests that the SDF-1-CXCR4 axis regulates the metastatic behavior of several malignancies including breast cancer, prostate cancer, lung cancer, and pediatric sarcomas (Libura et al., 2002, Kucia et al., 2005, Muller et al., 2001, Hartmann et al., 2005). In fact, cells from almost all cancer types were found to express CXCR4 and be responsive to SDF-1 gradient (Yasuoka et al., 2008, Ratajczak et al., 2006). Expression of CXCR4 on anaplastic or undifferentiated tumor cells and their responsiveness to SDF-1 gradient seems to mimic a role of the SDF-1-CXCR4 axis in developmental migration of pluripotent and organ-committed stem cells during embryogenesis. Because its expression on tumor cells is correlated with a poor prognosis in cancer patients (Zagzag et al., 2005, Staller et al., 2003, Li et al., 2004, Darash et al., 2004, Laverdire et al., 2005, Russell et al., 2004, Scala et al., 2005, Katmi et al., 2005, Katayama et al., 2005), the CXCR4 become a potential target for developing new anti-metastatic drugs (Takenaga et al., 2004, Tsutsumi et al., 2007). Of note, the CXCR4 was also identified as a co-receptor for entry of T tropic human immunodeficiency virus (HIV) into cells (Feng et al., 1996, Oberlin et al., 1996, Ding et al., 2008). SDF-1 binding to CXCR4 may interfere with that HIV entry.

Chromosomal mapping located RDC1 close to sequences encoding other chemokine receptors such as CXCR1, CXCR2, and CXCR4 on murine chromosome 1 and human chromosome 2, respectively (Heesen et al., 1998, Shimizu et al., 2000). For many years, RDC1 was considered an orphan receptor or a scavenger-type receptor for certain chemokines (Law and Rosenzweig, 1994). More was understood on a potential ligand for this receptor when RDC1 was expressed in cells that previously did not bind SDF-1 as well as when these RDC1⁺CXCR4⁻ cells were demonstrated as binding with high affinity SDF-1, which confirmed that RDC1 may indeed be a new receptor for SDF-1 (Burns et al., 2006). Furthermore, from several other chemokines tested, these CXCR7⁺ cells were also found to bind I-TAC (Burns et al., 2006).

Thus, after demonstrating that SDF-1 and I-TAC bind with high affinity to RDC1, RDC1 was officially “deorphanized” and renamed CXCR7 as a seventh receptor belonging to the CXC class of the chemokine receptor family (Balabanian et al., 2005, Burns et al. 2006). However, what must be kept in mind, I-TAC which is another CXCR7 ligand can also bind to chemokine receptor CXCR3 (Cole et al., 1998). Thus, any biological effects of I-TAC assigned to specific activation of the CXCR7 should be excluded from the possibility of this chemokine also engaging the CXCR3 receptor, if this receptor is expressed on target cells. In addition, it was confirmed that I-TAC may compete with SDF-1 for binding to CXCR7 and thus perturb the SDF-1-CXCR7 interaction.

First, the responsiveness of cells to SDF-1 gradient via CXCR4 and/or CXCR7 depends on surface expression of both receptors. While CXCR4 is expressed at the protein level on several types of cells, expression of CXCR7 is more abundant on embryonic and neoplastic transformed cells (Burns et al., 2006, Goldmann et al., 2008, Wang et al., 2008, Schutyser et al., 2007, and Miao et al. 2007). For example, it is still not clear whether CXCR7 is expressed on the surface of most primitive hematopoietic stem cells, which is in contrast to CXCR4. Second, CXCR4 has only one ligand, SDF-1, while CXCR7 also responds to I-TAC in addition to SDF-1. Thus, in contrast to CXCR4, CXCR7 is able to interact with two chemokines, SDF-1 and I-TAC, which both could compete for binding to CXCR7 (Burns et al., 2006). As such, SDF-1-mediated responses could be potentially modulated by I-TAC. Third, there are some reports that CXCR7 does not activate signal transduction in some cell types that, in contrast, are responsive to SDF-1 stimulation, for example (Sierro et al., 2007). In this context and with the association of CXCR7 with G_ai proteins still in controversy, it is not clear at this point if the SDF-1-CXCR7 axis is similar to the SDF-1-CXCR4 axis in sensitivity to pertussis toxin (Hartman et al., 2008). Furthermore, signaling of G-protein-coupled chemokine receptors is regulated by small proteins known as regulators of G-protein signaling (RGS) (Gold et al., 1997), despite expression of both receptors on the cell surface. Therefore, SDF-1 could activate this receptor only if it is not associated and thus “not muted” by its specific RGS proteins expressed in the given cell type. However, a potential RGS proteins for CXCR7, in contrast to those for CXCR4, were not yet described.

Finally, since the tissue concentration of SDF-1 is regulated by several factors such as for example hypoxia (Schioppa et al., 2003), the level of SDF-1 expression and its affinity for binding to particular receptors may decide whether the SDF-1-CXCR4 axis or the SDF-1-CXCR7 axis would be responsible for final SDF-1-mediated biological effect. As reported, SDF-1 has approximately 10 times higher affinity to CXCR7 as compared to CXCR4. In this context, it had been also described that responsiveness of CXCR4 to SDF-1 gradient may be positively modulated or primed by several small molecules related to inflammation, such as C3 complement cleavage fragments, for example (Wysoczynski et al., 2007, Reca et al., 2006). The molecular explanation for this phenomenon is observed in C3 cleavage fragments increasing incorporation of CXCR4 into membrane lipid rafts (Wysoczynski et al., 2005), which leads to dimerization and better association of CXCR4 incorporation into lipid rafts with downstream signaling molecules (Wysoczynski et al., 2007). It would be interesting to determine whether the responsiveness of CXCR7 to SDF-1 could be modulated by a similar phenomenon and if CXCR7 is a lipid raft-associated receptor.

Accordingly, it was reported that expression of CXCR7 on breast and lung cancer cells positively correlates with their proliferation, vascularization, and metastatic potential (Miao et al., 2007). CXCR7 was highly expressed on tumor-associated vessels, which is in contrast to endothelium unaffected by tumor tissues. While CXCR7-transduced murine human breast or lung cancer cell lines grow larger tumors in immunodeficient mice, downregulation of CXCR7 expression by siRNA resulted in formation of smaller tumors by these cells. CXCR7 over-expressing breast cancer cells also showed higher seeding efficiency to murine lungs in vivo (Miao et al., 2007).

In another recently published elegant study, CXCR7 was found to be highly expressed on human prostate cancer cells (Wang et al., 2008). Staining of high-density tissue microarrays demonstrated that CXCR7 expression at the protein level is higher on more aggressive tumors. Furthermore, studies on established prostate cancer cell lines revealed that CXCR7 regulates cell proliferation most likely because of enhanced cell survival, adhesion, and chemotaxis and, in addition, increases expression of proangiopoietic factors such as IL-8 and VEGF (Wang et al., 2008). Interestingly, the CXCR7 level was influenced in prostate cancer cells by CXCR4 activation. More importantly, evidence was also provided that CXCR7 signaling in prostate cancer cell lines results in phosphorylation of serine/theronine kinase Akt. Finally, prostate cancer cells overexpressing CXCR7 grew larger and better vascularized tumors in an immunodeficient mouse model (Wang et al., 2008).

With CXCR7 identified as a new receptor for SDF-1, our team became interested in a role of the SDF-1-CXCR7 axis in human RMS cells, which as previously described by us highly express CXCR4 and robustly respond to SDF-1 gradient and signaling (Libura et al., 2004). We found that CXCR7 was expressed at a high level by more primitive embryonic RMS cells lines (Libura et al., 2004). Overall, expression of CXCR7 was higher than CXCR4. More importantly, the CXCR7 on RMS cell lines was functional after stimulation with ITAC and SDF-1 as evidenced by MAPKp42/44- and Akt-phosphorylation, chemotaxis, cell motility, and adhesion assays. We also noticed that CXCR7 undergoes rapid internalization after stimulation with SDF-1 and ITAC. However, similarly to CXCR4 (Libura et al., 2004), we also found that signaling from activated CXCR7 was not associated with increased RMS proliferation or cell survival. Thus, CXCR7 signaling is mostly involved in RMS cell adhesion and motility and does not directly affect cell proliferation.

In prostate cancer cells, CXCR7 was also shown to affect expression of several molecules involved in tumor invasiveness such as CD44, cadherin-11, IL-8, VEGF, and tumor growth factor-beta (TGF-β) (Wang et al., 2008). Because CXCR7 could be upregulated on endothelial cells by hypoxia (Bosco et al., 2006, Costello et al., 2008) and considering its high expression on tumor-associated vessels (Madden et al., 2004), CXCR7 involvement in neoangiogensis and formation of tumor vasculature can be supported. SDF-1 is known as a strong chemoattractant for endothelial cells and this process has been assigned to stimulation of CXCR4 (Yamaguchi et al., 2003, Kucia et al., 2005). Thus, it is not clear at this point how important the interaction between SDF-1 and CXCR7 is in the chemoattraction of endothelial progenitors. In contrast to CXCR4, CXCR7 expression is relatively very low or undetectable on normal endothelial cells (Mazzinghi et al., 2008). As such, it is also not currently known whether CXCR7 is expressed on hemangioblasts and endothelial progenitors.

Expression of CXCR7 was found in embryonic, juvenile, and adult tissues. However, while CXCR7 is poorly expressed on normal somatic cells, its expression was found to be higher on transformed cells and during embryonic development in both human and murine tissues (Thelen and Thelen, 2008). Accordingly, CXCR7 as a protein is highly expressed on the surface of fetal liver cells, term placentas, activated endothelium, and on several murine and human tumor cell lines (Madden et al., 2004, Miao et al., 2007, Burns et al., 2006, Schutyser et al., 2007, Goldmann et al., 2008, Wang et al., 2008). Interestingly, non-transformed tissues express little membrane CXCR7 protein. In contrast, CXCR7 is detectable much more frequently at the mRNA level by Northern Blot. Accordingly, high levels of CXCR7 mRNA were found in heart, brain, spleen, kidney, lung, bladder, skeletal muscles, Langerhans islets, cartilage, synovium, testes, and ovary (Autelitano 1998, Martinez et al. 2000, Jones et al., 2006, Gerrits et al. 2008).

In the hematopoietic system, CXCR7 was reported to be expressed on neutrophils, monocytes, and B-cells (Balabanian et al., 2005, Sierro et al., 2007, Infantino et al., 2006). In B-cells, CXCR7 surface expression correlates with efficient differentiation into plasmocytes producing antibodies (Sierro et al., 2007). Interestingly, in contrast to CXCR4, CXCR7 is very weakly expressed on megakaryocytes and platelets (Ratajczak, not published observations). Data are also still missing on whether CXCR7 is also expressed on the surface of most primitive hematopoietic stem cells. For example, it is not clear at this point whether CXCR7 positive cells sorted from hematopoietic organs protect similarly to CXCR4 positive cells in lethally irradiated animals or if they are able to grow in vitro hematopoietic colonies in short-term colony forming and long-term culture assays (Ratajczak 2008).

It is known that activated chemokine receptors are internalized and subsequently degraded in the endosomal compartment or recycle to the cell surface (Kucia et al., 2005). Recent investigations on T-lymphocytes revealed that the majority of CXCR7 is present in the intracellular compartment in so-called early endosomes (Hartman et al., 2008). Therefore, more CXCR7 protein was detected if cells were permeabilized before staining (Hartman et al., 2008). Thus, these CXCR7 expression observations reveal that CXCR7 is regulated at several steps. Accordingly, cells that even highly express mRNA for CXCR7 may regulate its surface expression: i) at the translational level by regulating the rate of protein synthesis or ii) at the post-translational level by modulating its intracellular transporting and incorporation into the cell membrane. Finally, as mentioned previously, the question of whether the CXCR7 is lipid raft associated and/or regulated requires further study.

CXCR7 is also highly expressed in brain. In situ hybridization studies in rats revealed high expression in the forebrain in neuronal, astroglial, and vascular cells (Schönemeier et al., 2008). This suggests that SDF-1 may signal through CXCR7 in large populations of neural cells in brain.

In the first report, the majority of CXCR7 KD mice die perinatally due to severe ventricular and atrial septal defects and semilunar heart valve malformation (Sierro et al., 2007). In contrast, the tricuspid and mitral valves appeared normal at all stages examined (Sierro et al., 2007). The defects in semilunar valve development are explained by decreased expression of proangiopoietic adrenomedullin and heparin-binding epidermal growth factor (HB-EGF) in neonatal valve developing region (Sierro et al., 2007). Upon closer examination, it was found that the valves in affected animals were severely calcified, thickened, or fused. In addition, the affected mice often displayed an overriding aorta. Since no aberrant changes were revealed in embryonic hearths examined at day 17.5 of development, this suggests later CXCR7 involvement in the development of cardiac tissues (Sierro et al., 2007). Interestingly however, SDF-1 as well as its receptors CXCR7 and CXCR4 were found to be co-expressed in developing hearths, while only CXCR4 and CXCR7 are detectable in the valve developing region. Therefore, SDF-1-CXCR7 signaling appears to be critical for valve formation (Sierro et al., 2007). Theoretically some effects could potentially be related to I-TAC-CXCR7 interaction. However, because C57BL/6 mice are normal mutants lacking the I-TAC protein that develop normally in the absence of functional I-TAC, the I-TAC-CXCR7 interaction is unlikely to play a non-redundant role in organogenesis including valve formation.

In contrast, the second KD paper on CXCR7 deficient mice displayed a different cardiac phenotype (Gerrits et al., 2008). In that particular study, 50% of animals presented at autopsy with degenerated and fibrotic myocardium (Gerrits et al., 2008). These changes were even observed in some CXCR7^+/− heterozygotes. However, despite 70% lethality in first week of life, the remainder of KD mice had normal lifespans (Gerrits et al., 2008). Furthermore, 25% of these mice had enlarged hearts. Interestingly, no defects in valve formation were observed in these animals (Gerrits et al., 2008). The discrepancies between this and the previously discussed report could be explained by the different genetic background of animals employed for KD experiments. This also suggests that developmental defects are subtle and a final phenotype is modulated by several other factors. Curiously, in this second report, high expression of CXCR7 was found in osteocytes. However, despite high expression of CXCR4 in these cells, no skeletal defects were noticed, even in adult animals after performing ovariectomy or orchidectomy, which could potentially exacerbate subtle bone defects.

The role of CXCR7 in development of the cardiovascular system may somehow support CXCR7 morpholino oligomer KD results in zebrafish (Boldajipour et al., 2008). These animals were found to possess defects in pericardium and vessel development. To support a potential role of CXCR7 in vasculogenesis, CXCR7 valve defects observed in CXCR7 KD mice were recapitulated after selective CXCR7 deletion in the endothelium using Tie2-Cre transgenic mice (Sierro et al., 2007).

In contrast to the described CXCR4 mutation in humans (as seen in WHIM syndrome), spontaneous CXCR7 human mutations in have not been identified so far. However, based on the CXCR7 KD mice phenotype, potential CXCR7 mutations could be present in patients burdened with inherited cardiovascular disorders. Furthermore, since animal models revealed that CXCR7 could be involved in optimal migration of primordial germ cells (PGCs) (Boldajipour et al., 2008), CXCR7 could be potentially involved in some developmental pathologies of the reproductive system. This also requires further study.

The 5′ flanking sequence for the first two exons (untranslated and translated) possess features characteristic for promoter sequences, i.e., CpG islands and TATA-boxes. Our recent analysis of this putative CXCR7 promoter revealed that it contains several hypoxia inducible factor-1 alpha (HIF-1α) sites as well as a canonical nuclear factor kappa B (NF-κB) binding site. Our preliminary data also show an important role of this latter regulatory element in CXCR7 expression (manuscript in preparation). The presence of HIF-1α binding sites −155, −1012, beginning and −1350 base pairs upstream at of the transcription initiation site suggests that its expression could be regulated by hypoxia. To support this notion, it was found that CXCR7 expression could be unregulated in rat brain during ischemia in regions even distant from the stroke area (Schönemeier et al., 2008). On the other hand, CXCR7 expression directly in the stroke region was relatively scarce and associated with blood vessels (Schönemeier et al., 2008).

Generally but depending on cell type, CXCR7 was reported to either be a non-signaling or a signaling receptor. For example, it was postulated that CXCR7 is functional only when it dimerizes with other chemokine receptor partners (Mellado et al., 2001, Percherancier et al., 2005). To support this notion, the specific functionality was demonstrated by employing Förster resonance energy transfer (FRET) analysis of SDF-1-mediated physical heterodimerization of CXCR7 and CXCR4 on HEK293 cells (Sierro et al., 2007). Furthermore, co-expression of CXCR4 and CXCR7 on the same cells resulted in stronger calcium flux and more robust phosphorylation of MAPKp42/44 in response to SDF-1 stimulation as compared to cells that express CXCR4 only (Sierro et al., 2007). This could be explained by the heterodimeric receptor potentially being able to activate a broader panel of intracellular pathways than activation of one receptor only (Mellado et al., 2001), or by heterodimerization being able to modulate more robust intracellular responses of receptor specific pathways. This was shown in the case of MAPKp42/44 phosphorylation (Sierro et al., 2007).

Determining whether a similar phenomenon is more common in development and if it also plays a role in trafficking of other cells in adult organism requires further study. CXCR7 could behave like a member of the so-called interceptor family (Nibbs et al., 2003). Accordingly, interceptors possess high affinity of ligand binding, do not mediate signal transduction, and specialize in ligand scavenging through internalization. Thus, similarly to previously described interceptors such as Duffy blood group antigen/receptor for chemokines (DARC), D6 (Nibbs et al., 2003), and CCX-CKR (Comerford et al., 2006), CXCR7 may play a role as a molecular sink that controls the intercellular level of ligands and provides conditions facilitating the creation of sharp chemokine gradients. Molecular “sink activity” of CXCR7 could modulate or demarcate both SDF-1 and I-TAC gradients in several processes including: i) ischemia/reperfusion; ii) inflammation; iii) cell infiltration; and finally iv) proper cell migration during development.

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).