Institute for Science and Technology in Medicine, Keele University, Keele, Staffordshire ST5 5BG, UK.
School of Medicine, David Weatherall Building, Keele University, Staffordshire ST5 5BG, UK.
Mol Cell Neurosci. 2018 Jan;86:30-40. doi: 10.1016/j.mcn.2017.11.006. Epub 2017 Nov 9.
Corticosteroids (CSs) are widely used clinically, for example in pediatric respiratory distress syndrome, and immunosuppression to prevent rejection of stem cell transplant populations in neural cell therapy. However, such treatment can be associated with adverse effects such as impaired neurogenesis and myelination, and increased risk of cerebral palsy. There is increasing evidence that CSs can adversely influence key biological properties of neural stem cells (NSCs) but the molecular mechanisms underpinning such effects are largely unknown. This is an important issue to address given the key roles NSCs play during brain development and as transplant cells for regenerative neurology. Here, we describe the use of label-free quantitative proteomics in conjunction with histological analyses to study CS effects on NSCs at the cellular and molecular levels, following treatment with methylprednisolone (MPRED). Immunocytochemical staining showed that both parent NSCs and newly generated daughter cells expressed the glucocorticoid receptor, with nuclear localisation of the receptor induced by MPRED treatment. MPRED markedly decreased NSC proliferation and neuronal differentiation while accelerating the maturation of oligodendrocytes, without concomitant effects on cell viability and apoptosis. Parallel proteomic analysis revealed that MPRED induced downregulation of growth associated protein 43 and matrix metallopeptidase 16 with upregulation of the cytochrome P450 family 51 subfamily A member 1. Our findings support the hypothesis that some neurological deficits associated with CS use may be mediated via effects on NSCs, and highlight putative target mechanisms underpinning such effects.
皮质类固醇（CSs）在临床上被广泛应用，例如在儿科呼吸窘迫综合征和免疫抑制中，以防止神经细胞治疗中的干细胞移植人群发生排斥反应。然而，这种治疗可能会带来一些不良反应，如神经发生和髓鞘形成受损，以及脑瘫风险增加。越来越多的证据表明，CSs 可能会对神经干细胞（NSCs）的关键生物学特性产生不利影响，但这些影响的分子机制在很大程度上尚不清楚。考虑到 NSCs 在大脑发育过程中以及作为再生神经学的移植细胞所起的关键作用，这是一个需要解决的重要问题。在这里，我们描述了使用无标记定量蛋白质组学结合组织学分析来研究 MPRED 处理后 NSCs 在细胞和分子水平上的 CS 作用。免疫细胞化学染色显示，亲代 NSCs 和新生成的子细胞都表达了糖皮质激素受体，受体的核定位是由 MPRED 处理诱导的。MPRED 显著降低了 NSC 的增殖和神经元分化，同时加速了少突胶质细胞的成熟，而对细胞活力和凋亡没有影响。平行蛋白质组学分析显示，MPRED 诱导生长相关蛋白 43 和基质金属蛋白酶 16 的下调，同时细胞色素 P450 家族 51 亚家族 A 成员 1 的上调。我们的研究结果支持这样一种假设，即与 CS 使用相关的一些神经功能缺陷可能是通过对 NSCs 的作用介导的，并强调了潜在的作用机制。
