Extracellular Vesicles Derived from L-MYC Neural Stem Cells Mediate Neuroprotection in 3D Models of Chemotherapy- and Radiation-Induced Neurotoxicity
4 affiliations
- 1Department of Stem Cell Biology and Regenerative Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
- 2Department of Population Sciences and Supportive Care Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
- 3Department of Computational and Quantitative Medicine, Division of Mathematical Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
- 4Department of Radiation Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
Abstract
Background/Objectives: Cancer survivors frequently experience long-term neurocognitive impairments following chemotherapy and cranial irradiation, yet experimental models that enable mechanistic investigation of therapy-induced neurotoxicity at the transcriptional level remain limited. This study aimed to develop a human three-dimensional (3D) neural tissue model derived from L-MYC-immortalized neural stem cells (LMNSCs) and use transcriptomic profiling to identify molecular pathways underlying chemotherapy- and radiation-induced neural injury and extracellular vesicle (EV)-mediated recovery. Methods: LMNSCs were differentiated in a 3D, methylcellulose-based culture to generate neural tissue containing neurons, astrocytes, and oligodendrocytes in the absence of microglia. Cultures were exposed to methotrexate (MTX) or ionizing radiation to induce neural injury and subsequently treated with LMNSC-derived EVs. Neural injury and repair mechanisms were evaluated by immunocytochemistry and bulk transcriptomics. Results: MTX and irradiation induced dose-dependent injury, exhibited by loss of neuronal complexity and reduced glial populations. LMNSC-EV treatment promoted recovery of neuronal and glial populations following MTX- and irradiation-induced injury. Transcriptomic analysis of irradiated cultures revealed activation of inflammation, DNA damage, and stress-response pathways, which were attenuated after treatment with LMNSC-EVs. Conclusions: LMNSC-based 3D neural tissue provides a platform for modeling cancer therapy-induced neurotoxicity. Furthermore, LMNSC-EVs represent a promising cell-free regenerative therapeutic that modulates injury-associated inflammatory, stress, and metabolic transcriptional programs after radiation-induced neural injury.
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BibTeX
@article{nunes2026extracellular,
title = {{Extracellular Vesicles Derived from L-MYC Neural Stem Cells Mediate Neuroprotection in 3D Models of Chemotherapy- and Radiation-Induced Neurotoxicity}},
author = {Lance G. A. Nunes and Isabella Vasquez and Brecken Enright and Liv Chen and Sunita K. Patel and Russell C. Rockne and Stephanie Yoon and Margarita Gutova},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18213430},
url = {https://www.mdpi.com/2072-6694/18/21/3430},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Extracellular Vesicles Derived from L-MYC Neural Stem Cells Mediate Neuroprotection in 3D Models of Chemotherapy- and Radiation-Induced Neurotoxicity
AU - Lance G. A. Nunes
AU - Isabella Vasquez
AU - Brecken Enright
AU - Liv Chen
AU - Sunita K. Patel
AU - Russell C. Rockne
AU - Stephanie Yoon
AU - Margarita Gutova
PY - 2026
DA - 2026/10/23
JO - Cancers
DO - 10.3390/cancers18213430
UR - https://www.mdpi.com/2072-6694/18/21/3430
AB - Background/Objectives: Cancer survivors frequently experience long-term neurocognitive impairments following chemotherapy and cranial irradiation, yet experimental models that enable mechanistic investigation of therapy-induced neurotoxicity at the transcriptional level remain limited. This study aimed to develop a human three-dimensional (3D) neural tissue model derived from L-MYC-immortalized neural stem cells (LMNSCs) and use transcriptomic profiling to identify molecular pathways underlying chemotherapy- and radiation-induced neural injury and extracellular vesicle (EV)-mediated recovery. Methods: LMNSCs were differentiated in a 3D, methylcellulose-based culture to generate neural tissue containing neurons, astrocytes, and oligodendrocytes in the absence of microglia. Cultures were exposed to methotrexate (MTX) or ionizing radiation to induce neural injury and subsequently treated with LMNSC-derived EVs. Neural injury and repair mechanisms were evaluated by immunocytochemistry and bulk transcriptomics. Results: MTX and irradiation induced dose-dependent injury, exhibited by loss of neuronal complexity and reduced glial populations. LMNSC-EV treatment promoted recovery of neuronal and glial populations following MTX- and irradiation-induced injury. Transcriptomic analysis of irradiated cultures revealed activation of inflammation, DNA damage, and stress-response pathways, which were attenuated after treatment with LMNSC-EVs. Conclusions: LMNSC-based 3D neural tissue provides a platform for modeling cancer therapy-induced neurotoxicity. Furthermore, LMNSC-EVs represent a promising cell-free regenerative therapeutic that modulates injury-associated inflammatory, stress, and metabolic transcriptional programs after radiation-induced neural injury.
SN - 2072-6694
ER -