title: S1P promotes murine progenitor cell egress and mobilization via S1P1-mediated ROS signaling and SDF-1 release.
abstract: The mechanisms of hematopoietic progenitor cell egress and clinical mobilization are not fully understood. Herein, we report that in vivo desensitization of Sphingosine-1-phosphate (S1P) receptors by FTY720 as well as disruption of S1P gradient toward the blood, reduced steady state egress of immature progenitors and primitive Sca-1(+)/c-Kit(+)/Lin(-) (SKL) cells via inhibition of SDF-1 release. Administration of AMD3100 or G-CSF to mice with deficiencies in either S1P production or its receptor S1P(1), or pretreated with FTY720, also resulted in reduced stem and progenitor cell mobilization. Mice injected with AMD3100 or G-CSF demonstrated transient increased S1P levels in the blood mediated via mTOR signaling, as well as an elevated rate of immature c-Kit(+)/Lin(-) cells expressing surface S1P(1) in the bone marrow (BM). Importantly, we found that S1P induced SDF-1 secretion from BM stromal cells including Nestin(+) mesenchymal stem cells via reactive oxygen species (ROS) signaling. Moreover, elevated ROS production by hematopoietic progenitor cells is also regulated by S1P. Our findings reveal that the S1P/S1P(1) axis regulates progenitor cell egress and mobilization via activation of ROS signaling on both hematopoietic progenitors and BM stromal cells, and SDF-1 release. The dynamic cross-talk between S1P and SDF-1 integrates BM stromal cells and hematopoeitic progenitor cell motility.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Karin
authors.initials: K
authors.lastname: Golan
authors.forename: Yaron
authors.initials: Y
authors.lastname: Vagima
authors.forename: Aya
authors.initials: A
authors.lastname: Ludin
authors.forename: Tomer
authors.initials: T
authors.lastname: Itkin
authors.forename: Shiri
authors.initials: S
authors.lastname: Cohen-Gur
authors.forename: Alexander
authors.initials: A
authors.lastname: Kalinkovich
authors.forename: Orit
authors.initials: O
authors.lastname: Kollet
authors.forename: Chihwa
authors.initials: C
authors.lastname: Kim
authors.forename: Amir
authors.initials: A
authors.lastname: Schajnovitz
authors.forename: Yossi
authors.initials: Y
authors.lastname: Ovadya
authors.forename: Kfir
authors.initials: K
authors.lastname: Lapid
authors.forename: Shoham
authors.initials: S
authors.lastname: Shivtiel
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Mariusz Z
authors.initials: MZ
authors.lastname: Ratajczak
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
mesh_terms: D000818:Animals; D001596:Benzylamines; D001853:Bone Marrow / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism*; D003114:Colony-Forming Units Assay; D000080027:Cyclams; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006571:Heterocyclic Compounds; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000502:physiology*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D016179:Granulocyte Colony-Stimulating Factor; D006571:Heterocyclic Compounds; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D017382:Reactive Oxygen Species; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C515256:Cxcl12 protein, mouse; C060506:sphingosine 1-phosphate; C088327:plerixafor