Human Induced Pluripotent Stem Cells Re-Engineer the Study of Neurodevelopmental Disorders.
Human Induced Pluripotent Stem Cells Re-Engineer the Study of Neurodevelopmental Disorders.
复制标题
人类诱导多能干细胞重新设计神经发育障碍的研究。
DOI：
10.1016/j.jaac.2015.05.007
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发表时间：
2015
影响因子：
13.3
通讯作者：
Dranovsky,Alex
中科院分区：
文献类型：
--
作者：
Kim,EstherS;Dranovsky,Alex
在Shinya Yamanaka博士的团队于2007年发表的一篇开创性论文中，研究人员将人类皮肤成纤维细胞转化为多能干细胞，根据定义，多能干细胞可以自我更新（分裂产生更多干细胞）或分化为任何类型的细胞。因此，分化的细胞被“诱导”向后发育成多能干细胞。这种方法使科学家能够从患者或健康个体中产生诱导多能干细胞（iPSC），并将人特异性iPSC分化为任何感兴趣的细胞，包括人类神经元。在这一突破之前，活的人类神经元无法以这种能力进行研究。有了iPSC衍生的神经元，科学家们现在可以进行受控实验，以确定导致病理学的分子和结构变化，检查药物反应，并研究逆转病理学的方法。虽然皮肤成纤维细胞是用于产生iPSC的最充分表征的细胞类型，但包括血液单核细胞在内的其他细胞也被重编程为iPSC。由于iPSCs在生物医学领域的变革性影响，山中伸弥博士于2012年获得诺贝尔生理学或医学奖。在iPSCs问世之前，了解自闭症和精神分裂症等神经发育障碍的基础研究依赖于多种方法，包括患者神经成像、死后人体组织分析、转基因小鼠模型和细胞系，以研究疾病机制。人类神经成像提供了关于患者脑结构和功能的重要信息，但在阐明发病机制和治疗的细胞和分子机制方面的应用有限。转基因动物和体外细胞系统在机制研究中有很好的应用，但其结果与人类疾病的相关性尚不清楚。随着人类iPSC的发明，研究人员获得了一个独特的机会，通过使用与人类疾病有直接联系的细胞系来获得机制见解。还开发了将体细胞直接分化为神经元而不产生iPSC的方法。然而，由于其无限自我更新的能力，iPSC提供了一种可再生的干细胞资源，可以扩增，冷冻和分配，从而允许对单个患者进行无限数量的研究。
In a seminal paper by Dr. Shinya Yamanaka’s group in 20071, researchers transformed human skin fibroblasts into pluripotent stem cells, which by definition can self-renew (divide to produce more stem cells) or differentiate into any type of cell. Thus, differentiated cells were “induced” backward in development into pluripotent stem cells. This approach has enabled scientists to generate induced pluripotent stem cells (iPSCs) from patients or healthy individuals, and differentiate the person-specific iPSCs into any cell of interest, including human neurons. Until this breakthrough, live human neurons were inaccessible to study in this capacity. With iPSC-derived neurons, scientists can now perform controlled experiments to identify molecular and structural changes that contribute to pathology, examine drug responses, and investigate methods to reverse pathology. While skin fibroblasts are the most well-characterized cell type used to generate iPSCs, other cells including blood monocytes are also being reprogrammed into iPSCs. For iPSCs’ transformative impact in biomedical science, Dr. Yamanaka was awarded the Nobel Prize in Physiology or Medicine in 2012.Before iPSCs were available, basic research to understand neurodevelopmental disorders such as autism and schizophrenia had relied on several methods, including patient neuroimaging, post mortem human tissue analysis, transgenic mouse models, and cell lines, to investigate disease mechanisms. Human neuroimaging provides important information about patient brain structure and function but has limited application for elucidating cellular and molecular mechanisms of pathogenesis and treatment. Transgenic animals and in vitro cellular systems have excellent application for mechanistic studies, but the results have unclear relevance for human disease. With the invention of human iPSCs, investigators are given a unique opportunity to gain mechanistic insight by using cell lines with a direct link to human disease. Methods have also been developed to directly differentiate somatic cells into neurons without generating iPSCs. However, because of their capacity for indefinite self-renewal, iPSCs provide a renewable resource of stem cells that can be expanded, frozen, and distributed, thus allowing an unlimited number of studies from a single patient.