Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury
Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury
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DOI：
10.1634/stemcells.2006-0223
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发表时间：
2007-01-01
期刊：
影响因子：
5.2
通讯作者：
Sakata, Yoichi
中科院分区：
文献类型：
--
作者：
Kimura, Atsushi;Ohmori, Tsukasa;Sakata, Yoichi
神经干/祖细胞（NSPCs）迁移到中枢神经系统（CNS）的受损区域，以限制和/或修复损伤。尽管NSPCs的这种迁移特性在理论上可以用于CNS疾病的基于细胞的治疗，但对NSPCs迁移反应的机制知之甚少。在此，我们发现1-磷酸鞘氨醇（Sph-1-P），一种生理溶血磷脂介质，对NSPCs具有强的化学引诱活性，其中，Sph-1-P受体中，S1 P（1）大量表达。用百日咳毒素、Y-27632（Rho激酶抑制剂）和VPC 23019（S1 P（1）和S1 P（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不作为细胞内介质或以自分泌方式起作用，因为掺入NSPCs的[H-3]鞘氨醇主要在细胞内转化为神经酰胺和鞘磷脂，并且未观察到Sph-1-P的刺激依赖性形成和细胞外释放。此外，脊髓中的Sph-1-P浓度在挫伤后7天显著增加，这是由于损伤区域中小胶质细胞和反应性星形胶质细胞的积累。这种局部增加的Sph 1-P浓度有助于体内移植的NSPCs通过其受体S1 P的迁移（1），因为用短发夹RNA干扰S1 P的慢病毒转导NSPCs（1）消除了体内NSPC向损伤区域的迁移。这是第一个报告，以确定在NSPC迁移到中枢神经系统的病理区域的脂质介质的生理作用，并进一步表明，Sph-1-P/S1 P（1）途径可能具有治疗潜力的中枢神经系统损伤。
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 [H-3] 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 Sph1-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.