Cellular Reprogramming Unit, IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini, 71013, San Giovanni Rotondo, Foggia, Italy.
Department of Biotechnology and Biosciences, University of Milan Bicocca, Piazza della Scienza, 220126, Milan, Italy.
Cell Death Dis. 2018 Sep 17;9(10):937. doi: 10.1038/s41419-018-0990-2.
Establishing specific cell lineages from human induced pluripotent stem cells (hiPSCs) is vital for cell therapy approaches in regenerative medicine, particularly for neurodegenerative disorders. While neural precursors have been induced from hiPSCs, the establishment of hiPSC-derived human neural stem cells (hiNSCs), with characteristics that match foetal hNSCs and abide by cGMP standards, thus allowing clinical applications, has not been described. We generated hiNSCs by a virus-free technique, whose properties recapitulate those of the clinical-grade hNSCs successfully used in an Amyotrophic Lateral Sclerosis (ALS) phase I clinical trial. Ex vivo, hiNSCs critically depend on exogenous mitogens for stable self-renewal and amplification and spontaneously differentiate into astrocytes, oligodendrocytes and neurons upon their removal. In the brain of immunodeficient mice, hiNSCs engraft and differentiate into neurons and glia, without tumour formation. These findings now warrant the establishment of clinical-grade, autologous and continuous hiNSC lines for clinical trials in neurological diseases such as Huntington's, Parkinson's and Alzheimer's, among others.
从人诱导多能干细胞（hiPSCs）中建立特定的细胞谱系对于再生医学中的细胞治疗方法至关重要，特别是对于神经退行性疾病。虽然已经从 hiPSCs 中诱导出神经前体细胞，但尚未描述建立具有与胎 hNSCs 匹配的特征并符合 cGMP 标准的 hiPSC 衍生的人神经干细胞（hiNSCs），从而允许进行临床应用。我们通过无病毒技术生成 hiNSCs，其特性成功地再现了在肌萎缩侧索硬化症（ALS）I 期临床试验中成功使用的临床级 hNSCs。在体外，hiNSCs 严重依赖外源有丝分裂原来稳定自我更新和扩增，并在去除后自发分化为星形胶质细胞、少突胶质细胞和神经元。在免疫缺陷小鼠的大脑中，hiNSCs 植入并分化为神经元和神经胶质细胞，没有形成肿瘤。这些发现现在需要建立临床级、自体和连续的 hiNSC 系，用于亨廷顿氏病、帕金森氏病和阿尔茨海默氏病等神经疾病的临床试验。
