title: ALS disrupts spinal motor neuron maturation and aging pathways within gene co-expression networks.
abstract: 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.
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Ritchie
authors.initials: R
authors.lastname: Ho
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Sances
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Gowing
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Mackenzie Weygandt
authors.initials: MW
authors.lastname: Amoroso
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Jacqueline G
authors.initials: JG
authors.lastname: O'Rourke
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Anais
authors.initials: A
authors.lastname: Sahabian
authors.affiliation: Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, New York, USA.|Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
authors.forename: Hynek
authors.identifier: 0000-0002-7817-0080
authors.initials: H
authors.lastname: Wichterle
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.|Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Baloh
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.|Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Dhruv
authors.identifier: 0000-0002-0898-9656
authors.initials: D
authors.lastname: Sareen
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.|Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Clive N
authors.initials: CN
authors.lastname: Svendsen
mesh_terms: D000375:Aging; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000503:physiopathology; D015870:Gene Expression; D053263:Gene Regulatory Networks; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology; D009046:Motor Neurons / Q000166:cytology*; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*