Human cerebral organoids with microglia and vasculature model glioma stem cell interactions and radiotherapy response

Most human brain organoid models derived from induced pluripotent stem cells (iPSCs) lack vascular and/or immune components, despite their critical roles in maintaining brain homeostasis and contributing to pathophysiological processes. We established a method for generating vascularized complex cerebral organoids (CCOs) containing microglial cells (brain-resident macrophages) by incorporating bipotent hematopoietic/endothelial progenitors derived from the same iPSC lines. This approach led to the formation of extensive vascular-like structures with blood-brain barrier characteristics, which were perfused upon transplantation into immunodeficient mice. Additionally, microglial cells exhibiting typical phenotypes also developed within the CCOs. By co-culturing CCOs with glioma stem cells, we demonstrated that this model recapitulates the tumor niche of glioblastoma, showing vascular co-option, reprogramming of microglia into tumor-associated macrophages, and recurrence after radiotherapy. In conclusion, our vascularized, immunocompetent CCO model provides a platform to study brain development, glioma pathogenesis, and therapies.