Mesenchymal Stem Cell-Derived Factors Restore Function to Human Frataxin-Deficient Cells.
Mesenchymal Stem Cell-Derived Factors Restore Function to Human Frataxin-Deficient Cells.
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DOI：
10.1007/s12311-017-0860-y
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发表时间：
2017-08
期刊：
影响因子：
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通讯作者：
Wilkins A
中科院分区：
文献类型：
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作者：
Kemp K;Dey R;Cook A;Scolding N;Wilkins A
弗里德赖希共济失调是一种遗传性神经系统疾病，其特征是线粒体功能障碍和对氧化应激的易感性增加。目前，还没有任何治疗方法可以减少疾病的进展。正在试验的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少氧化损伤的药物。此外，干细胞已被研究作为一种潜在的治疗方法。我们使用siRNA诱导的SH-SY 5 Y细胞中共济失调蛋白的敲低作为弗里德赖希共济失调的体外细胞模型。实现了将共济失调蛋白表达敲低至在患有该病症的患者中检测到的水平，导致细胞活力降低、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。骨髓干细胞作为一种潜在的治疗广泛的神经系统疾病，包括弗里德赖希共济失调正在广泛的调查。因此，使用我们的共济失调蛋白缺陷细胞模型研究了骨髓来源的间充质干细胞的潜在神经保护作用。由间充质干细胞分泌的可溶性因子保护免受由共济失调蛋白缺乏诱导的细胞变化，导致共济失调蛋白水平和抗氧化防御的恢复，改善对氧化应激的存活，并刺激细胞增殖和雪旺细胞谱系的分化。间充质干细胞衍生因子可以恢复细胞内稳态和功能的证明进一步表明，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。
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.