Iyer Shilpa, Alsayegh Khaled, Abraham Sheena, Rao Raj R
Department of Neurology, University of Virginia, Charlottesville, Virginia, USA.
Crit Rev Biomed Eng. 2009;37(4-5):321-53. doi: 10.1615/critrevbiomedeng.v37.i4-5.20.
Multiple neurodegenerative disorders typically result from irrevocable damage and improper functioning of specialized neuronal cells or populations of neuronal cells. These disorders have the potential to contribute to an already overburdened health care system unless the progression of neurodegeneration can be altered. Progress in understanding neurodegenerative cell biology has been hampered by a lack of predictive and, some would claim, relevant cellular models. Additionally, the research needed to develop new drugs and determine methods for repair or replacement of damaged neurons is severely hampered by the lack of an adequate in vitro human neuron cell-based model. In this context, pluripotent stem cells and neural progenitors and their properties including unlimited proliferation, plasticity to generate other cell types, and a readily available source of cells--pose an excellent alternative to ex vivo primary cultures or established immortalized cell lines in contributing to our understanding of neurodegenerative cell biology and our ability to analyze the therapeutic or cytotoxic effects of chemicals, drugs, and xenobiotics. Many questions that define the underlying "genesis" of the neuronal death in these disorders also remain unanswered, with evidence suggesting a key role for mitochondrial dysfunction. The assessment of stem cells, neural progenitors, and engineered adult cells can provide useful insights into neuronal development and neurodegenerative processes. Finally, the potential for a combination of cell- and gene-based therapeutics for neurodegenerative disorders is also discussed.
多种神经退行性疾病通常源于特殊神经元细胞或神经元细胞群体的不可逆转损伤和功能异常。除非神经退行性变的进程能够改变，否则这些疾病有可能给本已不堪重负的医疗保健系统带来压力。由于缺乏可预测且有人认为相关的细胞模型，对神经退行性细胞生物学的理解进展受到阻碍。此外，由于缺乏适当的基于人源神经元细胞的体外模型，开发新药以及确定修复或替换受损神经元方法所需的研究也受到严重阻碍。在这种情况下，多能干细胞和神经祖细胞及其特性，包括无限增殖、生成其他细胞类型的可塑性以及易于获取的细胞来源，在帮助我们理解神经退行性细胞生物学以及分析化学物质、药物和外源性物质的治疗或细胞毒性作用方面，是体外原代培养或已建立的永生化细胞系的极佳替代选择。许多界定这些疾病中神经元死亡潜在“成因”的问题仍然没有答案，有证据表明线粒体功能障碍起关键作用。对干细胞、神经祖细胞和工程化成年细胞的评估可为神经元发育和神经退行性过程提供有用的见解。最后，还讨论了基于细胞和基因的联合疗法治疗神经退行性疾病的潜力。
