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.