S1P促进嗅鞘细胞增殖、迁移参与嗅球胶质屏障形成和神经再生

Olfactory ensheathing cells（OECs）transplantation has emerged as a promising experimental therapy for promoting the central nervous system repair after injury.The proliferation and motility of OECs is critical for neural regeneration and development of olfactory system. S1P (Sphingosine 1-phosphate), a diverse class of bioactive lipids, has been shown to promote neural regeneration of spinal cord injury. However, whether S1P regulates the proliferation, migration and neural regeneration of OECs remains unclear.Our preliminary data has shown that:①S1P receptors were highly expressed in OECs; ②S1P promotes the proliferation and migration of OECs. Based on these preliminary data, we propose our hypothesis: during development S1P promotes the proliferation and migration of OECs, to form the glia limitations in olfactory bulb, and OECs transplantation combining with S1P or receptor agonist are more effective to treat spinal cord injuries. To test this hypothesis, firstly,we will further examine the roles and mechanisms of S1P in OECs proliferation and migration using cellular and molecular technologies. Secondly, we will examine the physiological significance of SIP in formation and maintenance of OEC glia limitation based on S1P or S1PR1 knockout mice. Finally, we will examine whether OECs transplantation combining with S1P or receptor agonist are more effective to treat spinal cord injury based on spinal cord injuried animal model. These studies will provide novel insights and strategies of molecular mechanism of OECs development and OECs transplantation for treating injuries of nervous central systems.

移植嗅鞘细胞治疗脊髓损伤已显示具有潜在的临床应用前景，其增殖和迁移对促神经再生和嗅觉系统形成起关键作用。S1P是一种具有多种生物活性的鞘脂类代谢产物，能促进脊髓损伤修复，但是否对嗅鞘细胞增殖、迁移和促神经再生起作用尚不清楚。预实验发现:①S1P受体高表达于嗅鞘细胞；②S1P促进嗅鞘细胞增殖和迁移。由此设想：S1P促进嗅鞘细胞增殖和迁移，参与嗅鞘细胞发育；移植嗅鞘细胞联合S1P或受体激动剂治疗脊髓损伤具有协同作用。拟将采用细胞、分子生物学等技术进一步观察S1P对嗅鞘细胞增殖、迁移的作用和机制。其次，采用S1P或S1PR1基因敲除鼠，观察S1P对嗅球胶质屏障形成、维持的生理意义。最后，基于脊髓损伤模型，检测移植嗅鞘细胞联合S1P或受体激动剂治疗脊髓损伤是否具有协同作用。这些研究为阐明嗅鞘细胞发育的分子机制和嗅鞘细胞移植治疗中枢神经损伤的研究提供了新思路和新策略。

中枢神经损伤与再生修复一直是神经科学研究的热点和难点问题，脊髓损伤是较为常见的中枢神经损伤疾病。成年哺乳动物中枢神经系统再生非常困难，但嗅觉系统是一个特例。嗅鞘细胞可以迁移通过周围-中枢神经移行区，包裹神经纤维，并诱导神经元轴突的生长、再生和靶向。因此，寻找促嗅鞘细胞迁移和增殖的药物，联合嗅鞘细胞移植治疗脊髓损伤，有可能成为脊髓损伤治疗新手段和策略。S1P是一种具有多种生物活性的鞘脂类代谢产物，既可作为细胞内第二信使，直接调节细胞的相关靶点，又可分泌到细胞外，结合并激活细胞膜表面S1PRs发挥作用。许多研究发现，S1P/S1PR1可以促进脊髓损伤再生修复，但我们仍不清楚：1）S1P/S1PRs系统在嗅鞘细胞是否表达；2）该系统对嗅鞘细胞增殖和迁移是否有作用；3）移植嗅鞘细胞联合S1P或S1PR1激动剂，对于治疗脊髓损伤是否具有协同效应。本课题主要利用Yap条件性敲除小鼠、S1PR1的抑制剂W146和激动剂CYM5442、嗅鞘细胞移植技术等方法，研究S1P促进嗅鞘细胞增殖、迁移参与嗅球胶质屏障形成和神经再生的作用并探讨其相关分子机制。我们的实验基本证明在嗅鞘细胞正常发育过程中，S1P/S1PRs系统促进嗅鞘细胞增殖和迁移，参与嗅觉系统的形成；而在嗅鞘细胞移植联合S1P治疗脊髓损伤过程中，S1P通过促进嗅鞘细胞增殖和迁移，与S1P或S1PR1激动剂其他效应相互叠加、协同，更好地发挥促神经再生修复作用。