Kimura Atsushi, Ohmori Tsukasa, Ohkawa Ryunosuke, Madoiwa Seiji, Mimuro Jun, Murakami Takashi, Kobayashi Eiji, Hoshino Yuichi, Yatomi Yutaka, Sakata Yoichi
Department of Orthopedic Surgery, Jichi Medical University School of Medicine, Tochigi, Japan.
Stem Cells. 2007 Jan;25(1):115-24. doi: 10.1634/stemcells.2006-0223. Epub 2006 Sep 21.
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.
神经干细胞/祖细胞（NSPCs）会迁移至中枢神经系统（CNS）的损伤区域，以限制和/或修复损伤。尽管从理论上讲，NSPCs的这种迁移特性可用于中枢神经系统疾病的细胞治疗，但对于NSPCs迁移反应的机制却知之甚少。在此，我们发现，鞘氨醇-1-磷酸（Sph-1-P），一种生理性溶血磷脂介质，对NSPCs具有强大的趋化活性，其中，在Sph-1-P受体中，S1P(1)大量表达。百日咳毒素、Y-27632（一种Rho激酶抑制剂）和VPC23019（S1P(1)和S1P(3)的竞争性抑制剂）预处理可抑制Sph-1-P诱导的NSPC迁移。Sph-1-P并非作为细胞内介质或以自分泌方式发挥作用，因为掺入NSPCs的[(3)H]鞘氨醇在细胞内主要转化为神经酰胺和鞘磷脂，且未观察到Sph-1-P的刺激依赖性形成和细胞外释放。此外，由于损伤区域小胶质细胞和反应性星形胶质细胞的积聚，脊髓中的Sph-1-P浓度在挫伤损伤后7天显著增加。鉴于用针对S1P(1)的短发夹RNA干扰对NSPCs进行慢病毒转导消除了体内NSPCs向损伤区域的迁移，这种局部增加的Sph-1-P浓度通过其受体S1P(1)促进了体内移植的NSPCs的迁移。这是首次报道确定脂质介质在NSPCs向中枢神经系统病理区域迁移中的生理作用，并进一步表明Sph-1-P/S1P(1)途径可能对中枢神经系统损伤具有治疗潜力。
