INVESTIGATING NEUROINFLAMMATION IN TRAUMATIC INJURY USING HUMAN STEM-CELL DERIVED ORGANOID WITH AMYOTROPHIC LATERAL SCLEROSIS GENE MUTATION

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a typical survival of 3-5 years after symptom onset and no effective disease-modifying therapies. Epidemiological evidence links traumatic brain injury (TBI) to increased ALS risk, but the mechanisms by which TBI interacts with ALS-linked mutations to shape neuroinflammatory responses remain poorly defined. Conventional rodent models incompletely capture human-specific inflammatory and glial phenotypes, underscoring the need for human-relevant experimental systems.
The aim was to test whether ALS-linked mutations drive distinct neuroinflammatory trajectories after traumatic injury using a human induced pluripotent stem cell (iPSC)-derived cortical organoid model co-cultured with iPSC-derived microglia and astrocytes. Cortical organoids generated from iPSC lines harboring ALS-associated mutations (including FUS R495X) or isogenic/wild-type controls were subjected to a controlled traumatic impact paradigm. Neuroinflammatory responses were analyzed at 3-, 7-, and 14-day post-injury using cytokine profiling and immunofluorescence for glial markers and disease-associated proteins.
Traumatic impact successfully induced injury-related neuroinflammation across the genotypes, confirming the utility of this platform as a human model for TBI-ALS interactions. ALS-mutant organoids exhibited mutation-associated signatures, including altered temporal profiles of pro-inflammatory cytokine release and sustained oxidative stress at later time points. This study validates a genetically tractable human cortical organoid system for dissecting how ALS-linked mutations influence post-traumatic neuroinflammation and for future screening of mutation-targeted therapeutic strategies.