Transplantation of human pluripotent stem cell-derived pericytes ameliorates radiation-induced brain injury via CCR5 signaling

Radiation-induced brain injury remains an intractable complication of cranial radiotherapy, characterized by disrupted blood-brain barrier, inflammation, and progressive neuronal loss. Pericytes sustain severe damage in this pathology, yet no reliable repair treatment exists. Here we show that human pluripotent stem cell-derived pericytes exert therapeutic benefits in a mouse model of gamma knife radiation brain damage. Delivered intravenously at 4 and 6 weeks after irradiation, these cells reduce thalamic lesions, recover cerebral perfusion, and restore vascular pericyte coverage. The cells curb glial activation and lower pro-inflammatory cytokines. Transcriptomic analysis identifies CCR5 signaling as the core protective mechanism, which maintains neuronal and synaptic integrity partly by modulating downstream CREB activity. This study offers a feasible cell-based therapy and a distinct regulatory molecular pathway for cranial radiation brain injury treatment. All in vivo experiments were conducted using only male mice, and thus the observed therapeutic effects are only validated in male animals. We evaluate human pluripotent stem cell-derived cranial neural crest pericytes as therapy for mouse gamma knife-triggered radiation brain injury and investigate its regulatory mechanism. Intravenous cell delivery repairs brain vasculature, curbs neuroinflammation and protects neurons by modulating the CCR5/CREB axis, offering a practical cell treatment for radiation-induced brain injury.