Multiple sclerosis patient-derived CSF induces transcriptional changes in proliferating oligodendrocyte progenitors

This study provides an overview of the transcriptional signature of oligodendrocyte progenitor cells (OPCs) exposed to the CSF collected from multiple sclerosis patients with either a relapsing remitting disease course (RRMS) or a confirmed primary progressive diagnosis (PPMS). Using an Affymetrix microarray we were able to detect a set of common and unique genes for each treatment group. Gene ontology analysis revealed a common group of genes involved in protein transport, actin dynamics and response to stress and DNA damage, while the RRMS-specific genes were grouped according to protein complex biogenesis, nuclear transport and RNA processing. The transcriptional signature of progenitors exposed to PPMS was characterized by an up-regulation of the pro-differentiation adhesion molecule Lgals3. We confirmed increased protein levels of its gene product,product; galectin-3 in proliferating OPCs incubated with CSF from PPMS patients and also found a four-fold increase in mRNA transcript levels of galectin-3 in human post-mortem normal-appearing white matter samples of primary progressive MS patients when compared to non-neurological controls. This study will help to better understand the common and specific transcriptional changes induced in the different subtypes of MS and therefore find more specific molecular targets for each disease subtype.本研究针对暴露于复发缓解型多发性硬化（relapsing remitting multiple sclerosis, RRMS）或确诊原发进展型多发性硬化（primary progressive multiple sclerosis, PPMS）患者脑脊液（cerebrospinal fluid, CSF）的少突胶质细胞祖细胞（oligodendrocyte progenitor cells, OPCs）的转录特征展开概述。本研究采用Affymetrix基因芯片技术，成功检测得到各处理组共有的及特异性基因集合。基因本体（Gene Ontology, GO）分析结果显示，共有基因主要参与蛋白质转运、肌动蛋白动力学、应激应答与DNA损伤修复等生物学过程；而RRMS特异性基因则富集于蛋白质复合物生物发生、核转运及RNA加工等通路。暴露于PPMS患者脑脊液的祖细胞转录特征以促分化黏附分子Lgals3的上调为典型表现。我们进一步验证发现，经PPMS患者脑脊液孵育的增殖性OPCs中，该基因的编码产物半乳糖凝集素-3（galectin-3）的蛋白水平显著升高；同时相较于非神经系统疾病对照组，原发进展型MS患者死后脑组织外观正常的白质样本中，galectin-3的mRNA转录水平提升了四倍。本研究有助于更深入地理解不同多发性硬化亚型诱导的共有与特异性转录变化，进而为各疾病亚型筛选更具针对性的分子治疗靶点。