Goudarzi Salman, Rivera Andrea, Butt Arthur M, Hafizi Sassan
School of Pharmacy and Biomedical Sciences, Institute of Biomedical and Biomolecular Science, University of Portsmouth, UK.
School of Pharmacy and Biomedical Sciences, Institute of Biomedical and Biomolecular Science, University of Portsmouth, UK
ASN Neuro. 2016 Sep 14;8(5). doi: 10.1177/1759091416668430. Print 2016 Oct.
A key aim of therapy for multiple sclerosis (MS) is to promote the regeneration of oligodendrocytes and remyelination in the central nervous system (CNS). The present study provides evidence that the vitamin K-dependent protein growth arrest specific 6 (Gas6) promotes such repair in in vitro cultures of mouse optic nerve and cerebellum. We first determined expression of Gas6 and TAM (Tyro3, Axl, Mer) receptors in the mouse CNS, with all three TAM receptors increasing in expression through postnatal development, reaching maximal levels in the adult. Treatment of cultured mouse optic nerves with Gas6 resulted in significant increases in oligodendrocyte numbers as well as expression of myelin basic protein (MBP). Gas6 stimulation also resulted in activation of STAT3 in optic nerves as well as downregulation of multiple genes involved in MS development, including matrix metalloproteinase-9 (MMP9), which may decrease the integrity of the blood-brain barrier and is found upregulated in MS lesions. The cytoprotective effects of Gas6 were examined in in vitro mouse cerebellar slice cultures, where lysolecithin was used to induce demyelination. Cotreatment of cerebellar slices with Gas6 significantly attenuated demyelination as determined by MBP immunostaining, and Gas6 activated Tyro3 receptor through its phosphorylation. In conclusion, these results demonstrate that Gas6/TAM signaling stimulates the generation of oligodendrocytes and increased myelin production via Tyro3 receptor in the adult CNS, including repair after demyelinating injury. Furthermore, the effects of Gas6 on STAT3 signaling and matrix MMP9 downregulation indicate potential glial cell repair and immunoregulatory roles for Gas6, indicating that Gas6-TAM signaling could be a potential therapeutic target in MS and other neuropathologies.
多发性硬化症（MS）治疗的一个关键目标是促进少突胶质细胞的再生以及中枢神经系统（CNS）的髓鞘再生。本研究提供了证据表明，维生素K依赖性蛋白生长停滞特异性6（Gas6）在小鼠视神经和小脑的体外培养中促进这种修复。我们首先确定了Gas6和TAM（Tyro3、Axl、Mer）受体在小鼠中枢神经系统中的表达，所有三种TAM受体的表达在出生后发育过程中增加，在成年时达到最高水平。用Gas6处理培养的小鼠视神经导致少突胶质细胞数量以及髓鞘碱性蛋白（MBP）的表达显著增加。Gas6刺激还导致视神经中STAT3的激活以及参与MS发展的多个基因的下调，包括基质金属蛋白酶-9（MMP9），其可能会降低血脑屏障的完整性，并且在MS病变中上调。在体外小鼠小脑切片培养中检查了Gas6的细胞保护作用，其中溶血卵磷脂用于诱导脱髓鞘。通过MBP免疫染色确定，Gas6与小脑切片共同处理可显著减轻脱髓鞘，并且Gas6通过其磷酸化激活Tyro3受体。总之，这些结果表明，Gas6/TAM信号通过成年中枢神经系统中的Tyro3受体刺激少突胶质细胞的生成并增加髓鞘产生，包括脱髓鞘损伤后的修复。此外，Gas6对STAT3信号和基质MMP9下调的影响表明Gas6具有潜在的胶质细胞修复和免疫调节作用，表明Gas6-TAM信号可能是MS和其他神经病理学中的潜在治疗靶点。
