Abstract
Cancer survivors frequently experience long-term neurocognitive impairments following chemotherapy and cranial irradiation; however, clinically relevant experimental models that accurately recapitulate therapy-induced neurotoxicity are limited. In this study, we developed a human three-dimensional (3D) neural tissue model derived from L-MYC–immortalized human neural stem cells (LMNSCs) to investigate mechanisms of chemotherapy- and radiation-induced brain injury and to evaluate extracellular vesicle (EV)–mediated neuroprotection. LMNSC-derived cells in 3D cultures containing neuronal, glial, and oligodendrocyte progenitor populations were exposed to methotrexate or ionizing radiation to model cancer treatment-associated neurotoxicity. Cellular injury and lineage-specific vulnerability were assessed using flow cytometry, transcriptomic profiling, and molecular analyses of neural and glial markers. Both treatments induced significant damage to neuronal and oligodendroglial populations and altered transcriptional programs associated with neuroinflammation, synaptic function, and cellular stress responses. Treatment with neural stem cell–derived EVs promoted recovery of neural cell populations and partially restored transcriptional pathways involved in neuronal survival, neurogenesis, and tissue repair. These findings demonstrate that LMNSC-derived 3D neural tissue models provide a physiologically relevant platform for studying therapy-induced neurotoxicity and identifying regenerative interventions. Furthermore, our results support the potential of neural stem cell–derived EVs as a cell-free therapeutic strategy to mitigate chemotherapy- and radiation-induced brain injury. This platform may facilitate mechanistic studies and accelerate the development of neuroprotective therapies for cancer survivors.
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Dr. Margarita Gutova is an Assistant Professor in the Department of Stem Cell Biology and Regenerative Medicine at City of Hope. She leads a translational research program focused on developing neural stem cell-based and extracellular vesicle-based therapies for neurological diseases and brain tumors. Her work integrates human neural stem cell platforms, patient-derived tumor models, and advanced 3D brain tissue systems to study mechanisms of neuroprotection, neurotoxicity, and tumor–immune interactions. Dr. Gutova’s research aims to advance precision regenerative medicine and immunotherapy approaches for glioblastoma and cancer treatment-related neurocognitive impairments.
