Abstract
The first component of the complement (C) system C1q has multiple immune functions including acting as a chemoattractant for mature blood cells, and it has recently been reported that hematopoietic stem/progenitor cells (HSPC) express the C1q receptor, C1qRp. We have reported that the complement components C3 and C5 play an important role in the mobilization of HSPC and that G-CSF mobilization activates C by the classical Ig-dependent pathway (
Blood 2004;103:2071
; Stem Cells 2007, in press). While C3 plays an important role in the retention of HSPC in BM, C5 is pivotal for their egress into peripheral blood. The aim of this study was to examine a possible role for C1q in the mobilization/homing of HSPC. We found (using RT-PCR and Western blotting) that the C1q gene and protein are strongly expressed in human mobilized peripheral blood (mPB) CD34+ cells, but not in steady-state bone marrow (BM) CD34+ cells. Importantly, we found that G-CSF stimulation of BM cells induces the expression of C1q in CD34+ cells, as detected by flow cytometry. Moreover, we demonstrated the presence of the receptor for C1q, C1qRp, in BM, mPB and cord blood (CB) CD34+ cells as well as in myeloid, megakaryocytic and erythroid progenitors ex vivo-expanded from CD34+ cells. The stromal derived factor (SDF)-1-CXCR4 axis plays a critical role in HSPC homing to BM and we showed using confocal microscopy that pre-incubation (for 1 h) of CB CD34+ cells on C1q-coated slides increased incorporation of the SDF-1 receptor, CXCR4, into membrane lipid rafts while C1q-coated filters increased chemoattraction (compared to bare filters) to an SDF-1 gradient. Although C1q itself is not a chemoattractant for HSPC, it primed the chemotactic response of CD34+ cells to a low SDF-1 gradient (10 ng/mL) to the extent that it approximated response to a high SDF-1 gradient (200 ng/mL), as well as the chemoinvasion of CB CD34+ cells across reconstituted basement membrane (Matrigel) to a low gradient of SDF-1, which was inhibited by the monoclonal anti-C1q antibody. In addition, C1q stimulated matrix-degrading metalloproteinase-9 secretion by CB CD34+ cells. In conclusion, we demonstrated for the first time that G-CSF mobilization strongly upregulates C1q in human HSPC which express the functional C1q receptor and that the first component of the complement cascade is involved in HSPC trafficking. This supports our previous data that C as an important modulator of the SDF-1-CXCR4 axis plays a pivotal role in the mobilization of HSPC.Author notes
Disclosure: No relevant conflicts of interest to declare.
2007, The American Society of Hematology
2007
