National Centre for Adult Stem Cell Research, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Queensland, Australia.
Stem Cells. 2012 Nov;30(11):2361-5. doi: 10.1002/stem.1220.
Traditional models of brain diseases have had limited success in driving candidate drugs into successful clinical translation. This has resulted in large international pharmaceutical companies moving out of neuroscience research. Cells are not brains, obviously, but new patient-derived stem models have the potential to elucidate cell biological aspects of brain diseases that are not present in worm, fly, or rodent models, the work horses of disease investigations and drug discovery. Neural stem cells are present in the olfactory mucosa, the organ of smell in the nose. Patient-derived olfactory mucosa has demonstrated disease-associated differences in a variety of brain diseases and recently olfactory mucosa stem cells have been generated from patients with schizophrenia, Parkinson's disease, and familial dysautonomia. By comparison with cells from healthy controls, patient-derived olfactory mucosa stem cells show disease-specific alterations in gene expression and cell functions including: a shorter cell cycle and faster proliferation in schizophrenia, oxidative stress in Parkinson's disease, and altered cell migration in familial dysautonomia. Olfactory stem cell cultures thus reveal patient-control differences, even in complex genetic diseases such as schizophrenia and Parkinson's disease, indicating that multiple genes of small effect can converge on shared cell signaling pathways to present as a disease-specific cellular phenotype. Olfactory mucosa stem cells can be maintained in homogeneous cultures that allow robust and repeatable multiwell assays suitable for screening libraries of drug candidate molecules.
传统的脑疾病模型在推动候选药物成功转化为临床应用方面收效甚微。这导致大型国际制药公司退出神经科学研究。显然，细胞不是大脑，但新的患者来源的干细胞模型有可能阐明在蠕虫、苍蝇或啮齿动物模型（疾病研究和药物发现的主要工具）中不存在的大脑疾病的细胞生物学方面。神经干细胞存在于嗅黏膜中，即鼻子的嗅觉器官。源自患者的嗅黏膜已在多种脑疾病中表现出与疾病相关的差异，最近已从精神分裂症、帕金森病和家族性自主神经异常患者中生成了嗅黏膜干细胞。与来自健康对照者的细胞相比，源自患者的嗅黏膜干细胞在基因表达和细胞功能方面显示出疾病特异性改变，包括：精神分裂症中细胞周期更短和增殖更快、帕金森病中的氧化应激以及家族性自主神经异常中的细胞迁移改变。嗅黏膜干细胞培养物因此揭示了患者与对照者之间的差异，即使是在复杂的遗传疾病（如精神分裂症和帕金森病）中，这表明多个小效应基因可以汇聚到共享的细胞信号通路，表现为特定疾病的细胞表型。嗅黏膜干细胞可以在同质培养物中维持，这些培养物允许进行强大且可重复的多孔板测定，适用于候选药物分子文库的筛选。
