ROCK Inhibitor Y27632 Induced Morphological Shift and Enhanced Neurite Outgrowth-Promoting Property of Olfactory Ensheathing Cells via YAP-Dependent Up-Regulation of L1-CAM
ROCK Inhibitor Y27632 Induced Morphological Shift and Enhanced Neurite Outgrowth-Promoting Property of Olfactory Ensheathing Cells via YAP-Dependent Up-Regulation of L1-CAM
复制标题
DOI：
10.3389/fncel.2018.00489
复制
发表时间：
2018-12-11
影响因子：
5.3
通讯作者：
Xu, Haiwei
中科院分区：
文献类型：
--
作者：
Li, Yijian;Huo, Shujia;Xu, Haiwei
嗅鞘细胞（OECs）在形态、抗原谱和功能上是异质的，并且这些OEC亚群在OEC移植治疗中枢神经系统（CNS）损伤后显示出不同的结果。在形态学上，嗅鞘细胞可分为两个亚群，即具有突起的（雪旺细胞样）和扁平的（星形胶质细胞样）嗅鞘细胞，它们可以在彼此之间转换，并受到细胞外和细胞内因素的影响。然而，OECs的形态与功能之间的关系及其分子机制尚未阐明。在本研究中，我们首先研究了不同细胞因子暴露条件下嗅鞘细胞的形态和功能差异。结果表明，在促炎条件下（脂多糖，LPS），OEC主要显示出一个过程轴承形状，而在抗炎条件下，它们显示出一个扁平的形状[白细胞介素-4（IL-4）和转化生长因子-β 1（TGF-β 1）]。形态学变化是部分可逆的，Rho相关的卷曲螺旋蛋白激酶（ROCK）/F-actin途径参与。在功能上，与抗炎条件下的扁平OECs相比，促炎条件下的过程轴承OECs显示出增加的细胞代谢活性和更高的迁移率，并显着促进神经突生长和延伸。值得注意的是，ROCK抑制剂Y27632诱导的朝向过程轴承OECs的形态转变增强了OECs的神经突生长促进特性。此外，转录共激活因子Yes相关蛋白（雅普）作为ROCK信号通路的下游，通过上调神经粘附分子L1-CAM的表达，介导嗅鞘细胞的形态学改变，增强其促进轴突生长的特性。我们的数据提供了证据表明，具有特定形状的OECs对应于特定的功能表型，并为OECs和小分子ROCK抑制剂用于CNS损伤再生的潜在组合开辟了新的见解。
Olfactory ensheathing cells (OECs) are heterogeneous in morphology, antigenic profiles and functions, and these OEC subpopulations have shown different outcomes following OEC transplantation for central nervous system (CNS) injuries. Morphologically, OECs are divided into two subpopulations, process-bearing (Schwann cells-like) and flattened (astrocytes-like) OECs, which could switch between each other and are affected by extracellular and intracellular factors. However, neither the relationship between the morphology and function of OECs nor their molecular mechanisms have been clarified. In the present study, we first investigated morphological and functional differences of OECs under different cytokine exposure conditions. It demonstrated that OECs mainly displayed a process-bearing shape under pro-inflammatory conditions (lipopolysaccharide, LPS), while they displayed a flattened shape under anti-inflammatory conditions [interleukin-4 (IL-4) and transforming growth factor-beta 1 (TGF-beta 1)]. The morphological changes were partially reversible and the Rho-associated coiled-coil-containing protein kinase (ROCK)/F-actin pathway was involved. Functionally, process-bearing OECs under pro-inflammatory conditions showed increased cellular metabolic activity and a higher migratory rate when compared with flattened OECs under anti-inflammatory conditions and significantly promoted neurite outgrowth and extension. Remarkably, the morphological shift towards process-bearing OECs induced by ROCK inhibitor Y27632 enhanced the neurite outgrowth-promoting property of OECs. Furthermore, as the downstream of the ROCK pathway, transcriptional co-activator Yes-associated protein (YAP) mediated morphological shift and enhanced the neurite outgrowth-promoting property of OECs through upregulating the expression of the neural adhesion molecule L1-CAM. Our data provided evidence that OECs with specific shapes correspond to specific functional phenotypes and opened new insights into the potential combination of OECs and small-molecule ROCK inhibitors for the regeneration of CNS injuries.