Novel insight into stem cell mobilization-plasma sphingosine-1-phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization due to activation of complement cascade/membrane attack complex.
The 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 chemoattractant present in peripheral blood (PB) is responsible for the egress of HSPCs from the bone marrow (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 the 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 interaction of the 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 through MAC induces the release of S1P from erythrocytes for optimal egress/mobilization of HSPCs.
Ratajczak
M Z
MZ
Stem Cell Biology Program at the James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA. mzrata01@louisville.edu
Lee
H
H
Wysoczynski
M
M
Wan
W
W
Marlicz
W
W
Laughlin
M J
MJ
Kucia
M
M
Janowska-Wieczorek
A
A
Ratajczak
J
J
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D001596:Benzylamines; D001853:Bone Marrow / Q000378:metabolism*; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000097:blood; D003114:Colony-Forming Units Assay; D003167:Complement Activation; D003182:Complement C5 / Q000502:physiology*; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D000080027:Cyclams; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006358:Hot Temperature; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
D019380:Anti-HIV Agents; D001596:Benzylamines; D054377:Chemokine CXCL12; D003182:Complement C5; D015938:Complement Membrane Attack Complex; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D008246:Lysophospholipids; D019718:Receptors, CXCR4; C060506:sphingosine 1-phosphate; D013110:Sphingosine; C088327:plerixafor