S1P promotes murine progenitor cell egress and mobilization via S1P 1-mediated ROS signaling and SDF-1 release

Karin Golan, Yaron Vagima, Aya Ludin, Tomer Itkin, Shiri Cohen-Gur, Alexander Kalinkovich, Orit Kollet, Chihwa Kim, Amir Schajnovitz, Yossi Ovadya, Kfir Lapid, Shoham Shivtiel, Andrew J. Morris, Mariusz Z. Ratajczak, Tsvee Lapidot

Research output: Contribution to journalArticlepeer-review

162 Scopus citations

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 S1P1, 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 S1P1 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/S1P1 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.

Original languageEnglish
Pages (from-to)2478-2488
Number of pages11
JournalBlood
Volume119
Issue number11
DOIs
StatePublished - Mar 15 2012

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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