Sphingosine-1-phosphate-mediated mobilization of hematopoietic stem/progenitor cells during intravascular hemolysis requires attenuation of SDF-1-CXCR4 retention signaling in bone marrow.
Sphingosine-1-phosphate (S1P) is a crucial chemotactic factor in peripheral blood (PB) involved in the mobilization process and egress of hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM). Since S1P is present at high levels in erythrocytes, one might assume that, by increasing the plasma S1P level, the hemolysis of red blood cells would induce mobilization of HSPCs. To test this assumption, we induced hemolysis in mice by employing phenylhydrazine (PHZ). We observed that doubling the S1P level in PB from damaged erythrocytes induced only a marginally increased level of mobilization. However, if mice were exposed to PHZ together with the CXCR4 blocking agent, AMD3100, a robust synergistic increase in the number of mobilized HSPCs occurred. We conclude that hemolysis, even if it significantly elevates the S1P level in PB, also requires attenuation of the CXCR4-SDF-1 axis-mediated retention in BM niches for HSPC mobilization to occur. Our data also further confirm that S1P is a major chemottractant present in plasma and chemoattracts HSPCs into PB under steady-state conditions. However, to egress from BM, HSPCs first have to be released from BM niches by blocking the SDF-1-CXCR4 retention signal.
Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Room 107, Louisville, KY 40202, USA ; Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
Kasia
K
Mierzejewska
Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY 40536, USA.
Yuri M
YM
Klyachkin
Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Room 107, Louisville, KY 40202, USA ; Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
Janina
J
Ratajczak
Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY 40536, USA.
Ahmed
A
Abdel-Latif
Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Room 107, Louisville, KY 40202, USA ; Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
Magda
M
Kucia
Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Room 107, Louisville, KY 40202, USA.
Mariusz Z
MZ
Ratajczak
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057510:Endovascular Procedures; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006461:Hemolysis; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D008246:Lysophospholipids; D019718:Receptors, CXCR4; C060506:sphingosine 1-phosphate; D013110:Sphingosine