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. 2025 Jul 3;32(7):1139-1153.e7.
doi: 10.1016/j.stem.2025.05.015. Epub 2025 Jun 24.

An organ-chip model of sporadic ALS using iPSC-derived spinal cord motor neurons and an integrated blood-brain-like barrier

Deepti Lall  1 , Michael J Workman  1 , Samuel Sances  1 , Briana N Ondatje  1 , Shaughn Bell  1 , George Lawless  1 , Amanda Woodbury  1 , Dylan West  1 , Amanda Meyer  1 , Andrea Matlock  2 , Vineet Vaibhav  2 , Jennifer E Van Eyk  2 , Clive N Svendsen  3
Affiliations

An organ-chip model of sporadic ALS using iPSC-derived spinal cord motor neurons and an integrated blood-brain-like barrier

Deepti Lall et al. Cell Stem Cell. .

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder in which motor neurons (MNs) of the brain and spinal cord degenerate, leading to paralysis. Generating MNs from patient-specific induced pluripotent stem cells (iPSCs) may help elucidate early stages of disease. Here, we combined MNs from patients with early-onset disease with brain microvascular endothelial-like cells in a microfluidic device we termed spinal cord chips (SC-chips) and added media flow, which enhanced neuronal maturation and improved cellular health. Bulk transcriptomic and proteomic analyses of SC-chips revealed differences between control and ALS samples, including increased levels of neurofilaments. Single-nuclei RNA sequencing revealed the presence of two MN subpopulations and an ALS-specific dysregulation of glutamatergic and synaptic signaling. This ALS SC-chip model generates a diversity of mature MNs to better understand ALS pathology in a model that has an active blood-brain barrier-like system for future drug screening.

Keywords: amyotrophic lateral sclerosis; glutamatergic synapse; microfluidic organ-chips; motor neuron identity; neuronal maturation; synaptic signaling.

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Conflict of interest statement

Declaration of interests Cedars-Sinai owns a minority stock interest in Emulate, the company that produces the study’s microfluidic organ-chips. An officer of Cedars-Sinai also serves on Emulate’s Board of Directors. C.N.S. serves on the advisory board of Cell Stem Cell.

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