Radiation-induced fate shift of neural progenitors toward endothelial-like cells in human cortical organoids

SUMMARY/ABSTRACT Cranial radiotherapy remains a cornerstone for treating primary and metastatic brain tumors. However, it is frequently associated with long-term cognitive decline, particularly in patients who survive beyond six months post-treatment. Despite advances in radiation delivery and neuroprotective strategies, no effective interventions currently exist to prevent or reverse radiation-induced neurotoxicity. The studies outlined in this proposal are based on a novel hypothesis that radiation disrupts neural lineage commitment in the developing human brain, driving aberrant cellular plasticity and transdifferentiation of neural stem/progenitor cells into endothelial-like phenotypes, which is supported by preliminary and published data. These fate shifts impair neurodevelopment and alter synaptic function, contributing to long-term cognitive deficits. The overall hypothesis is that radiation-induced cellular reprogramming in the human brain alters both cellular identity and functional connectivity, and that these effects can be mitigated through targeted inhibition of endothelial-inductive pathways (e.g., VEGF, FGFR, Notch). To test this, we will use mature human iPSC-derived cortical organoids subjected to fractionated radiation and apply single-cell and spatial transcriptomic approaches to define lineage transitions (Aim 1), followed by functional assays including calcium imaging and multielectrode array recordings to assess neural network activity in the presence and absence of pathway inhibition (Aim 2). This R21 project leverages cutting-edge 3D human brain models and state-of-the-art technologies to address a major gap in understanding the cellular mechanisms underlying radiation-induced cognitive impairment. Because the targeted pathways have existing pharmacologic inhibitors already in clinical use, this research has high translational potential for developing radiation mitigators to preserve brain function in cancer patients undergoing radiotherapy. Project Number: 1R21CA312903-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Ling He | Institution: UNIVERSITY OF CALIFORNIA LOS ANGELES, LOS ANGELES, CA | Award Amount: $368,156 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CTH-N (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11354475