title: Sphingosine-1-phosphate facilitates trafficking of hematopoietic stem cells and their mobilization by CXCR4 antagonists in mice.
abstract: CXCL12 and VCAM1 retain hematopoietic stem cells (HSCs) in the BM, but the factors mediating HSC egress from the BM to the blood are not known. The sphingosine-1-phosphate receptor 1 (S1P(1)) is expressed on HSCs, and S1P facilitates the egress of committed hematopoietic progenitors from the BM into the blood. In the present study, we show that both the S1P gradient between the BM and the blood and the expression of S1P(1) are essential for optimal HSC mobilization by CXCR4 antagonists, including AMD3100, and for the trafficking of HSCs during steady-state hematopoiesis. We also demonstrate that the S1P(1) agonist SEW2871 increases AMD3100-induced HSC and progenitor cell mobilization. These results suggest that the combination of a CXCR4 antagonist and a S1P(1) agonist may prove to be sufficient for mobilizing HSCs in normal donors for transplantation purposes, potentially providing a single mobilization procedure and eliminating the need to expose normal donors to G-CSF with its associated side effects.
authors: Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney, Australia.
authors: Julius G
authors: JG
authors: Juarez
authors: Nadia
authors: N
authors: Harun
authors: Marilyn
authors: M
authors: Thien
authors: Robert
authors: R
authors: Welschinger
authors: Rana
authors: R
authors: Baraz
authors: Aileen Dela
authors: AD
authors: Pena
authors: Stuart M
authors: SM
authors: Pitson
authors: Michael
authors: M
authors: Rettig
authors: John F
authors: JF
authors: DiPersio
authors: Kenneth F
authors: KF
authors: Bradstock
authors: Linda J
authors: LJ
authors: Bendall
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D001596:Benzylamines; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D016207:Cytokines / Q000378:metabolism; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase
chemical_list: D019380:Anti-HIV Agents; D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D016207:Cytokines; D004338:Drug Combinations; D016179:Granulocyte Colony-Stimulating Factor; D006571:Heterocyclic Compounds; D008246:Lysophospholipids; D009842:Oligopeptides; D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; D019718:Receptors, CXCR4; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase; C556330:S1pr1 protein, mouse; C504129:TC14012; C060506:sphingosine 1-phosphate; C088327:plerixafor