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TISSUE-SPECIFIC STEM CELLS

Essential Roles of Sphingosine 1-Phosphate/S1P₁ Receptor Axis in the Migration of Neural Stem Cells Toward a Site of Spinal Cord Injury

^aDepartment of Orthopedic Surgery, Jichi Medical University School of Medicine, Tochigi, Japan;
^bResearch Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University School of Medicine, Tochigi, Japan;
^cDivision of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical University School of Medicine, Tochigi, Japan;
^dDepartment of Laboratory Medicine, The University of Tokyo School of Medicine, Tokyo, Japan

Key Words. Migration • Neural stem cell • Transplantation • Lysophospholipid

Correspondence: Tsukasa Ohmori, M.D., Ph.D., Research Division of Cell and Molecular Medicine, Center for Molecular Medicine Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan. Telephone: +81-285-58-7398; Fax: +81-285-44-7817; e-mail: tohmori{at}jichi.ac.jp

Received April 14, 2006; accepted for publication September 9, 2006.
First published online in STEM CELLS EXPRESS   September 21, 2006.



Neural stem/progenitor cells (NSPCs) migrate toward a damaged area of the central nervous system (CNS) for the purpose of limiting and/or repairing the damage. Although this migratory property of NSPCs could theoretically be exploited for cell-based therapeutics of CNS diseases, little is known of the mechanisms responsible for migratory responses of NSPCs. Here, we found that sphingosine 1-phosphate (Sph-1-P), a physiological lysophospholipid mediator, had a potent chemoattractant activity for NSPCs, in which, of Sph-1-P receptors, S1P₁ was abundantly expressed. Sph-1-P-induced NSPC migration was inhibited by the pretreatment with pertussis toxin, Y-27632 (a Rho kinase inhibitor), and VPC23019 (a competitive inhibitor of S1P₁ and S1P₃). Sph-1-P does not act as intracellular mediator or in an autocrine manner, because [³H]sphingosine, incorporated into NSPCs, was mainly converted to ceramide and sphingomyeline intracellularly, and the stimulation-dependent formation and extracellular release of Sph-1-P were not observed. Further, Sph-1-P concentration in the spinal cord was significantly increased at 7 days after a contusion injury, due to accumulation of microglia and reactive astrocytes in the injured area. This locally increased Sph-1-P concentration contributed to the migration of in vivo transplanted NSPCs through its receptor S1P₁, given that lentiviral transduction of NSPCs with a short hairpin RNA interference for S1P₁ abolished in vivo NSPC migration toward the injured area. This is the first report to identify a physiological role for a lipid mediator in NSPC migration toward a pathological area of the CNS and further indicates that the Sph-1-P/S1P₁ pathway may have therapeutic potential for CNS injuries.