Disease-specific, neurosphere-derived cells as models for brain disorders
Disease-specific, neurosphere-derived cells as models for brain disorders
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DOI：
10.1242/dmm.005447
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发表时间：
2010-11-01
影响因子：
4.3
通讯作者：
Mackay-Sim, Alan
中科院分区：
文献类型：
--
作者：
Matigian, Nicholas;Abrahamsen, Greger;Mackay-Sim, Alan
迫切需要患者来源的脑疾病细胞模型，这些模型足够相关和强大，可以产生分子和功能分析所需的大量细胞。我们在这里描述了一种新的细胞模型，该模型基于来自人类嗅觉粘膜（嗅觉器官）的患者来源的细胞，该细胞在整个生命过程中从神经干细胞再生。嗅粘膜活检标本来自健康对照组和患有精神分裂症（一种神经发育性精神障碍）或帕金森病（一种神经退行性疾病）的患者。将活检组织分离并在限定培养基中生长为神经球。神经球衍生的细胞系在含血清培养基中生长为粘附单层并冷冻储存。通过比较42个患者和对照细胞系，我们证明了基因表达，蛋白质表达和细胞功能的显着疾病特异性改变，包括精神分裂症中的神经发育途径失调和帕金森病中的线粒体功能失调，氧化应激和异生物质代谢。这项研究已经确定了新的候选基因和细胞通路，供未来研究使用。精神分裂症患者的成纤维细胞没有显示出这些差异。嗅神经球源性细胞作为脑疾病的模型具有许多优于胚胎干细胞和诱导多能干细胞的优点。它们不需要基因重编程，并且可以从患有复杂遗传疾病的成年人中获得。它们将有助于了解疾病的病因，诊断和药物发现。
There is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery.