Kemp Kevin, Dey Rimi, Cook Amelia, Scolding Neil, Wilkins Alastair
Multiple Sclerosis and Stem Cell Group, School of Clinical Sciences, Clinical Neurosciences office, University of Bristol, 1st floor, Learning and Research building, Southmead Hospital, Bristol, BS10 5NB, UK.
Cerebellum. 2017 Aug;16(4):840-851. doi: 10.1007/s12311-017-0860-y.
Friedreich's ataxia is an inherited neurological disorder characterised by mitochondrial dysfunction and increased susceptibility to oxidative stress. At present, no therapy has been shown to reduce disease progression. Strategies being trialled to treat Friedreich's ataxia include drugs that improve mitochondrial function and reduce oxidative injury. In addition, stem cells have been investigated as a potential therapeutic approach. We have used siRNA-induced knockdown of frataxin in SH-SY5Y cells as an in vitro cellular model for Friedreich's ataxia. Knockdown of frataxin protein expression to levels detected in patients with the disorder was achieved, leading to decreased cellular viability, increased susceptibility to hydrogen peroxide-induced oxidative stress, dysregulation of key anti-oxidant molecules and deficiencies in both cell proliferation and differentiation. Bone marrow stem cells are being investigated extensively as potential treatments for a wide range of neurological disorders, including Friedreich's ataxia. The potential neuroprotective effects of bone marrow-derived mesenchymal stem cells were therefore studied using our frataxin-deficient cell model. Soluble factors secreted by mesenchymal stem cells protected against cellular changes induced by frataxin deficiency, leading to restoration in frataxin levels and anti-oxidant defences, improved survival against oxidative stress and stimulated both cell proliferation and differentiation down the Schwann cell lineage. The demonstration that mesenchymal stem cell-derived factors can restore cellular homeostasis and function to frataxin-deficient cells further suggests that they may have potential therapeutic benefits for patients with Friedreich's ataxia.
弗里德赖希共济失调是一种遗传性神经障碍，其特征为线粒体功能障碍以及对氧化应激的易感性增加。目前，尚无疗法被证明可减缓疾病进展。正在试验用于治疗弗里德赖希共济失调的策略包括改善线粒体功能和减轻氧化损伤的药物。此外，干细胞已作为一种潜在的治疗方法进行了研究。我们利用小干扰RNA诱导SH-SY5Y细胞中frataxin基因敲低，作为弗里德赖希共济失调的体外细胞模型。将frataxin蛋白表达敲低至该疾病患者中检测到的水平，导致细胞活力下降、对过氧化氢诱导的氧化应激的易感性增加、关键抗氧化分子的失调以及细胞增殖和分化的缺陷。骨髓干细胞作为包括弗里德赖希共济失调在内的多种神经障碍的潜在治疗方法正在被广泛研究。因此，我们使用我们的frataxin缺陷细胞模型研究了骨髓间充质干细胞的潜在神经保护作用。间充质干细胞分泌的可溶性因子可保护细胞免受frataxin缺乏诱导的细胞变化影响，导致frataxin水平和抗氧化防御功能恢复，提高对氧化应激的存活率，并刺激雪旺细胞谱系的细胞增殖和分化。间充质干细胞衍生因子可恢复frataxin缺陷细胞的细胞稳态和功能这一证明进一步表明，它们可能对弗里德赖希共济失调患者具有潜在的治疗益处。
