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

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, 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. STEM CELLS 2007;25:115-124

Antagonism of Sphingosine 1-Phosphate Receptor-2 Enhances Migration of Neural Progenitor Cells Toward an Area of Brain Infarction

“…Interestingly, the addition of S1P inhibited the NPC migration elicited by a higher concentration of VPC24191 (1 to 10 mol/L; Figure 4C). These data suggest that S1P 1 R is the primary receptor involved in S1P-mediated NPC migration, in support of our previous study, 6 but also indicated that other S1PRs can regulate the S1P 1 R-mediated response.…”

“…18,19 We previously showed a role for S1P in NPC migration toward a pathologic area of the CNS and proposed that elevation of S1P at the site of injury was a guiding factor for NPC migration. 6 Here, we reveal that S1P 2 R is a potential target for strategies aiming to increase NPC migration after brain ischemia.…”

“…6 In brief, the forebrains of E14.5 mouse embryos were isolated and mechanically dissociated into a suspension of single cells. The dissociated cells were cultured in Dulbecco's modified Eagle's medium/F12 supplemented with B27 supplement (Invitrogen, Carlsbad, Calif), 20 ng/mL basic fibroblast growth factor, and 20 ng/mL endothelial growth factor.…”

“…6 S1P is currently attracting a great deal of attention as a bioactive sphingolipid that has various cellular functions and acts via the 7 transmembrane S1P receptors (S1PRs), S1P 1 R through S1P 5 R. [7][8][9] We reported that the S1P concentration in the spinal cord increased after a contusion injury and contributed to the migration of transplanted NPCs in vivo via the S1P 1 R. 6 In the current study, we show that S1P-mediated NPC migration toward an area of brain injury is enhanced by modulation of S1P 2 R function. We propose new therapeutic approaches to enhance the mobilization of endogenous NPCs toward areas of CNS injury.…”

Emerging Therapies for Multiple Sclerosis

“…In a rat model of spinal cord injury, S1P concentration was locally increased and contributed to the attraction of neural stem cells via the S1P 1 receptor. 60 At the present time, differences in study design, outcome measures and patient populations preclude comparing the efficacy of FTY720 with other disease-modifying agents. Two phase III studies in MS are currently ongoing.…”