Essential Roles of Sphingosine 1-phosphate/1P₁ Receptor Axis in the Migration of Neural Stem Cells toward a Site of Spinal Cord Injury

¹ Department of Orthopedic Surgery Research, Jichi Medical University School of Medicine, Tochigi, Japan; Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University School of Medicine, Tochigi, Japan; Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical University School of Medicine, Tochigi, Japan
² Research Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University School of Medicine, Tochigi, Japan
³ Department of Laboratory Medicine, The University of Tokyo School of Medicine, Tokyo, Japan
⁴ Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical University School of Medicine, Tochigi, Japan
⁵ Department of Orthopedic Surgery, Jichi Medical University School of Medicine, Tochi, Japan

^* To whom correspondence should be addressed. E-mail: tohmori{at}jichi.ac.jp.

	Abstract

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, where, 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, since lentiviral transduction of NSPCs with a shRNAi 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.

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