We postulate that mobilization of hematopoietic stem cells (HSC) is part of a immune-response and to support this notion i) complement (C) cascade cleavage fragments modulate trafficking of HSC (

Blood
2003
;
101
,
3784
;
Blood
2004
;
103
,
2071
) and ii) patients suffering from severe combined immunodeficiency (SCID) are poor mobilizers (
Blood
1996
;
88
,
1104
). To shed more light on mechanisms involved in C-mediated trafficking of HSC we studied mobilization in several strains of immune-deficient mice mobilized by employing various mobilization protocols. We noticed that mobilization of HSC is always preceded by C activation - occuring by the classical (G-CSF, CY) or alternative (polysaccharides, chemokines) activation pathways. Accordingly, the classical pathway of C activation after G-CSF or CY administration is a result of proteolytic modification of the BM environment leading to the exposure of a neo-antigen in BM tissue, and binding of natural IgM antibodies to this neo-epitope triggers activation of the C cascade. In support of this, IgM-deficient mice (SCID, RAG2null and Jh) are poor mobilizers and G-CSF-induced mobilization in these mice was restored after supplementation with purified C-activating inmmunoglobulins. On the other hand the mobilization in these mice (SCID, RAG2null and Jh) was normal in response to polysaccharides or chemokines that activate complement by the alternative IgM-independent pathway. To further support an important role of C in HSC mobilization, we studied HSC mobilization in mice deficient for various C components (C3−/− and C5−/− mice). We noticed that C3−/− mice are easy mobilizers. In contrast mobilization was very poor in C5−/− mice. This suggests that C3 and C5 cleavage fragments differently control the mobilization of HSC. We will present evidence that C3 cleavage fragments directly interact with HSC and prevent their uncontrolled egress from BM during mobilization by increasing their SDF-1-dependent marrow retention. In contrast C5 cleavage fragments activate neutrophils and BM-endothelium and thus are crucial for the egress of HSC. Thus the mobilization of HSC is i) dependent on C activation by the classical or alternative pathway, ii) modified differently by C3 cleavage fragments which enhance retention and C5 cleavage fragments which promote egress of HSC. Thus modulation of C activation in BM may help to develop new more efficient strategies for both HSC mobilization and their homing/engraftment.

Topics:
complement system proteins, cytokinesis, hematopoietic stem cells, immunologic deficiency syndromes, mice, severe combined immunodeficiency, chemokines, granulocyte colony-stimulating factor, immunoglobulin m, polysaccharides

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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