Open AccessEssential Roles of Sphingosine 1‐Phosphate/S1P 1 Receptor Axis in the Migration of Neural Stem Cells Toward a Site of Spinal Cord Injury
Author(s) -
Kimura Atsushi,
Ohmori Tsukasa,
Ohkawa Ryunosuke,
Madoiwa Seiji,
Mimuro Jun,
Murakami Takashi,
Kobayashi Eiji,
Hoshino Yuichi,
Yatomi Yutaka,
Sakata Yoichi
Publication year - 2007
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1634/stemcells.2006-0223
Subject(s) - biology , microbiology and biotechnology , progenitor cell , sphingosine 1 phosphate , lipid signaling , sphingosine , neural stem cell , cell migration , stem cell , receptor , cell , biochemistry
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, S1P 1 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 S1P 1 and S1P 3 ). Sph‐1‐P does not act as intracellular mediator or in an autocrine manner, because [ 3 H]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 S1P 1 , given that lentiviral transduction of NSPCs with a short hairpin RNA interference for S1P 1 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/S1P 1 pathway may have therapeutic potential for CNS injuries.