Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury.
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.
Kimura
Atsushi
A
Department of Orthopedic Surgery, Jichi Medical University School of Medicine, Tochigi, Japan.
Ohmori
Tsukasa
T
Ohkawa
Ryunosuke
R
Madoiwa
Seiji
S
Mimuro
Jun
J
Murakami
Takashi
T
Kobayashi
Eiji
E
Hoshino
Yuichi
Y
Yatomi
Yutaka
Y
Sakata
Yoichi
Y
D000818:Animals; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000502:physiology*; D008246:Lysophospholipids / Q000378:metabolism; D009474:Neurons / Q000637:transplantation*; D016548:Prosencephalon / Q000166:cytology / Q000196:embryology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000628:therapy*; D033581:Stem Cell Transplantation
D008246:Lysophospholipids; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013110:Sphingosine