Ho Ritchie, Sances Samuel, Gowing Genevieve, Amoroso Mackenzie Weygandt, O'Rourke Jacqueline G, Sahabian Anais, Wichterle Hynek, Baloh Robert H, Sareen Dhruv, Svendsen Clive N
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.
Nat Neurosci. 2016 Sep;19(9):1256-67. doi: 10.1038/nn.4345. Epub 2016 Jul 18.
Modeling amyotrophic lateral sclerosis (ALS) with human induced pluripotent stem cells (iPSCs) aims to reenact embryogenesis, maturation and aging of spinal motor neurons (spMNs) in vitro. As the maturity of spMNs grown in vitro compared to spMNs in vivo remains largely unaddressed, it is unclear to what extent this in vitro system captures critical aspects of spMN development and molecular signatures associated with ALS. Here, we compared transcriptomes among iPSC-derived spMNs, fetal spinal tissues and adult spinal tissues. This approach produced a maturation scale revealing that iPSC-derived spMNs were more similar to fetal spinal tissue than to adult spMNs. Additionally, we resolved gene networks and pathways associated with spMN maturation and aging. These networks enriched for pathogenic familial ALS genetic variants and were disrupted in sporadic ALS spMNs. Altogether, our findings suggest that developing strategies to further mature and age iPSC-derived spMNs will provide more effective iPSC models of ALS pathology.
利用人类诱导多能干细胞（iPSC）建立肌萎缩侧索硬化症（ALS）模型旨在体外重现脊髓运动神经元（spMN）的胚胎发生、成熟和衰老过程。与体内的spMN相比，体外培养的spMN的成熟度在很大程度上仍未得到解决，目前尚不清楚这种体外系统在何种程度上捕捉到了spMN发育的关键方面以及与ALS相关的分子特征。在此，我们比较了iPSC衍生的spMN、胎儿脊髓组织和成人脊髓组织之间的转录组。这种方法产生了一个成熟度量表，显示iPSC衍生的spMN与胎儿脊髓组织比与成人spMN更相似。此外，我们解析了与spMN成熟和衰老相关的基因网络和通路。这些网络富集了致病性家族性ALS基因变异，并在散发性ALS的spMN中被破坏。总之，我们的研究结果表明，制定进一步使iPSC衍生的spMN成熟和老化的策略将提供更有效的ALS病理学iPSC模型。
