The Research Institute, Nationwide Children's Hospital, Columbus, OH 43205.
Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):829-32. doi: 10.1073/pnas.1314085111. Epub 2013 Dec 30.
Amyotrophic lateral sclerosis (ALS) causes motor neuron degeneration, paralysis, and death. Accurate disease modeling, identifying disease mechanisms, and developing therapeutics is urgently needed. We previously reported motor neuron toxicity through postmortem ALS spinal cord-derived astrocytes. However, these cells can only be harvested after death, and their expansion is limited. We now report a rapid, highly reproducible method to convert adult human fibroblasts from living ALS patients to induced neuronal progenitor cells and subsequent differentiation into astrocytes (i-astrocytes). Non-cell autonomous toxicity to motor neurons is found following coculture of i-astrocytes from familial ALS patients with mutation in superoxide dismutase or hexanucleotide expansion in C9orf72 (ORF 72 on chromosome 9) the two most frequent causes of ALS. Remarkably, i-astrocytes from sporadic ALS patients are as toxic as those with causative mutations, suggesting a common mechanism. Easy production and expansion of i-astrocytes now enables rapid disease modeling and high-throughput drug screening to alleviate astrocyte-derived toxicity.
肌萎缩侧索硬化症（ALS）会导致运动神经元退化、瘫痪和死亡。目前迫切需要准确的疾病建模、确定疾病机制和开发治疗方法。我们之前曾报道过通过对死后 ALS 脊髓源性星形胶质细胞进行研究，发现运动神经元毒性。然而，这些细胞只能在死后采集，而且其扩增受到限制。现在我们报告了一种快速、高度可重复的方法，可将来自活的 ALS 患者的成人成纤维细胞转化为诱导性神经祖细胞，随后分化为星形胶质细胞（i-astrocytes）。在将携带超氧化物歧化酶突变或 C9orf72 六核苷酸扩增（9 号染色体上的 ORF72）的家族性 ALS 患者的 i-astrocytes 与突变体共培养后，发现其对运动神经元具有非细胞自主毒性。这两种突变是 ALS 最常见的病因。值得注意的是，散发性 ALS 患者的 i-astrocytes 与具有致病突变的 i-astrocytes 一样具有毒性，这表明存在共同的机制。i-astrocytes 的易于生产和扩增现在可以实现快速疾病建模和高通量药物筛选，以减轻星形胶质细胞衍生的毒性。
