Complement cascade (CC) becomes activated and its cleavage fragments play a crucial role in the mobilization of hematopoietic stem/progenitor cells (HSPCs). Here, we sought to determine which major chemottractant present in peripheral blood (PB) is responsible for the egress of HSPCs from the BM. We noticed that normal and mobilized plasma strongly chemoattracts HSPCs in a stromal derived factor-1 (SDF-1)-independent manner because i) plasma SDF-1 level does not correlate with mobilization efficiency, ii) the chemotactic plasma gradient is not affected in the presence of AMD3100, and iii) it is resistant to denaturation by heat. Surprisingly, the observed loss of plasma chemotactic activity after charcoal stripping suggested involvement of bioactive lipids and we focused on sphingosine-1 phosphate (S1P), a known chemoattracant of HSPCs. We found that S1P i) creates in plasma a continuously present gradient for BM-residing HSPCs, ii) is at physiologically relevant concentrations a chemoattractant several magnitudes stronger than SDF-1, and iii) its plasma level increases during mobilization due to CC activation and the interaction of membrane attack complex (MAC) with erythrocytes that are a major reservoir of S1P. We conclude and propose a new paradigm that S1P is a crucial chemoattractant for BM-residing HSPCs and that CC via MAC induces release of S1P from erythrocytes for optimal egress/mobilization of HSPCs.

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