Temporal mapping of radiation-induced neural injury and mitigation in human cortical organoids.

Overview

1. Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, United States
2. Department of Psychiatry and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, United States
3. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, United States
4. Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, United States
5. Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, United States

Abstract

Background: Radiation therapy is a standard-of-care oncological treatment for central nervous system (CNS) malignancies. However, as survival outcomes improve, radiation-induced injury to normal brain tissue has increased in clinical significance. CNS radiation injury is a delayed, multifactorial process characterized by impaired neurogenesis, reactive gliosis, and persistent functional deficits. Mechanistic exploration and development of effective radiation mitigators have been limited by the lack of scalable, human-relevant models.

Methods: Mature human iPSC-derived cortical organoids were exposed to single-dose or clinically relevant fractionated radiation (5 × 2 Gy). DNA damage, apoptosis, and growth dynamics were assessed longitudinally. Structural organization, synaptic integrity, and neuroinflammatory responses were evaluated by immunofluorescence and real-time PCR. Transcriptomic profiling was performed at 72 hours and 2 weeks after fractionated radiation to capture acute and delayed effects. Two candidate radiation mitigators, NSPP and amisulpride, were tested for their therapeutic effects within the organoid system.

Results: Cortical organoids exhibited partial recovery following single doses up to 4 Gy or fractioned irradiation. Transcriptomic analyses revealed that radiation not only reduced overall cell viability but also reshaped lineage trajectories, characterized by depletion of neural stem/progenitor populations, loss of neuronal identity, enhanced gliogenesis, increased inflammatory cytokines, and disrupted cortical layering and synaptic integrity. Treatment with NSPP or amisulpride attenuated injury-associated transcriptional and structural alterations.

Conclusion: Human cortical organoids recapitulate key features of radiation-induced neural injury, recovery, and therapeutic modulation, providing a robust, scalable, and human-relevant platform for studying CNS radiation biology and preclinical screening of candidate radiation mitigators.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

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Data

Datasets cited

• geo:GSE295097, at NCBI GEO; found in “Data availability”

Data availability

The sequencing data have been submitted to Gene Expression Omnibus and are available with the following Accession Number: GSE295097 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE295097).

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 4 authors, 6 keywords, 7 MeSH terms, 2 funders, 54 references.

Cite

This paper

He, L., Kornblum, H. I., Bhaduri, A., & Pajonk, F. (2026). Temporal mapping of radiation-induced neural injury and mitigation in human cortical organoids. Stem cells translational medicine, 15(9), szag071. https://doi.org/10.1093/stcltm/szag071

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