Neuroimmunology Unit, Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Department of Neurosurgery, McGill University Health Centre and Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Ann Neurol. 2022 Feb;91(2):178-191. doi: 10.1002/ana.26288. Epub 2022 Jan 10.
Myelin regeneration in the human central nervous system relies on progenitor cells within the tissue parenchyma, with possible contribution from previously myelinating oligodendrocytes (OLs). In multiple sclerosis, a demyelinating disorder, variables affecting remyelination efficiency include age, severity of initial injury, and progenitor cell properties. Our aim was to investigate the effects of age and differentiation on the myelination potential of human OL lineage cells.
We derived viable primary OL lineage cells from surgical resections of pediatric and adult brain tissue. Ensheathment capacity using nanofiber assays and transcriptomic profiles from RNA sequencing were compared between A2B5+ antibody-selected progenitors and mature OLs (non-selected cells).
We demonstrate that pediatric progenitor and mature cells ensheathed nanofibers more robustly than did adult progenitor and mature cells, respectively. Within both age groups, the percentage of fibers ensheathed and ensheathment length per fiber were greater for A2B5+ progenitors. Gene expression of OL progenitor markers PDGFRA and PTPRZ1 were higher in A2B5+ versus A2B5- cells and in pediatric A2B5+ versus adult A2B5+ cells. The p38 MAP kinases and actin cytoskeleton-associated pathways were upregulated in pediatric cells; both have been shown to regulate OL process outgrowth. Significant upregulation of "cell senescence" genes was detected in pediatric samples; this could reflect their role in development and the increased susceptibility of pediatric OLs to activating cell death responses to stress.
Our findings identify specific biological pathways relevant to myelination that are differentially enriched in human pediatric and adult OL lineage cells and suggest potential targets for remyelination enhancing therapies. ANN NEUROL 2022;91:178-191.
在人体中枢神经系统中，髓鞘再生依赖于组织实质内的祖细胞，可能还有先前髓鞘形成的少突胶质细胞（OL）的贡献。在脱髓鞘疾病多发性硬化症中，影响髓鞘再生效率的变量包括年龄、初始损伤的严重程度和祖细胞特性。我们的目的是研究年龄和分化对人 OL 谱系细胞的髓鞘形成潜力的影响。
我们从儿科和成人脑组织的手术切除中获得了可行的原代 OL 谱系细胞。使用纳米纤维测定法比较了 A2B5+抗体选择的祖细胞和成熟 OL（非选择细胞）的包被能力，并通过 RNA 测序的转录组谱进行了比较。
我们证明，儿科祖细胞和成熟细胞比成人祖细胞和成熟细胞分别更有力地包被纳米纤维。在两个年龄组中，A2B5+祖细胞包被的纤维百分比和每根纤维的包被长度都更大。A2B5+细胞中 OL 祖细胞标记物 PDGFRA 和 PTPRZ1 的表达高于 A2B5-细胞，儿科 A2B5+细胞中高于成人 A2B5+细胞。p38 MAP 激酶和肌动蛋白细胞骨架相关途径在儿科细胞中上调；这两者都被证明可以调节 OL 突起的生长。在儿科样本中检测到“细胞衰老”基因的显著上调；这可能反映了它们在发育中的作用，以及儿科 OL 对激活应激后细胞死亡反应的敏感性增加。
我们的研究结果确定了与髓鞘形成相关的特定生物学途径，这些途径在人儿科和成人 OL 谱系细胞中差异富集，并为增强髓鞘再生的治疗提供了潜在的靶点。ANN NEUROL 2022;91:178-191.
