Functional equivalence of stem cell and stem cell-derived extracellular vesicle transplantation to repair the irradiated brain

Abstract

Abstract Cranial radiotherapy, although beneficial for the treatment of brain tumors, inevitably leads to normal tissue damage that can induce unintended neurocognitive complications that are progressive and debilitating. Ionizing radiation exposure has also been shown to compromise the structural integrity of mature neurons throughout the brain, an effect believed to be at least in part responsible for the deterioration of cognitive health. Past work has shown that cranially transplanted human neural stem cells (hNSCs) or their extracellular vesicles (EVs) afforded long-term beneficial effects on many of these cognitive decrements. To provide additional insight into the potential neuroprotective mechanisms of cell-based regenerative strategies, we have analyzed hippocampal neurons for changes in structural integrity and synaptic remodeling after unilateral and bilateral transplantation of hNSCs or EVs derived from those same cells. Interestingly, hNSCs and EVs similarly afforded protection to host neurons, ameliorating the impact of irradiation on dendritic complexity and spine density for neurons present in both the ipsilateral and contralateral hippocampi 1 month following irradiation and transplantation. These morphometric improvements were accompanied by increased levels of glial cell-derived growth factor and significant attenuation of radiation-induced increases in postsynaptic density protein 95 and activated microglia were found ipsi- and contra-lateral to the transplantation sites of the irradiated hippocampus treated with hNSCs or hNSC-derived EVs. These findings document potent far-reaching neuroprotective effects mediated by grafted stem cells or EVs adjacent and distal to the site of transplantation and support their potential as therapeutic agents to counteract the adverse effects of cranial irradiation. Significance statement Cranial radiation therapy for the treatment of brain cancers often leads to adverse impacts on cognitive function. This is particularly problematic for childhood cancer survivors who live long post-therapy lives. The past regenerative medicine approaches using human neural stem cells (hNSCs) have shown beneficial neurocognitive effects in the irradiated brain. The present study evaluated the neuroprotective impact of hNSCs and hNSC-derived extracellular vesicles in the irradiated brain, as demonstrated by preservation of host neuronal morphology, reductions in inflammation, and restoration of neurotrophic factors.