Human brain cellular xenografts in neuroimmunology and beyond

Human brain cellular xenograft (HBCX) models are emerging as a platform to study human brain physiology and pathology in vivo. HBCXs involve transplanting human pluripotent stem cell-derived neurons, glia, or organoids into immunodeficient mice to model human disease. These models have revealed human-specific cellular and molecular phenotypes, developmental trajectories, and disease mechanisms that would otherwise be inaccessible in traditional in vitro systems and animal models. They also provide a scalable, genetically editable framework for functional genomics studies, drug testing, and biomarker discovery. Given the pronounced species differences in microglia and other tissue-resident brain macrophages and their central involvement in neurodegenerative disease, these models also provide an in vivo platform to interrogate human neuroimmunology. In selected settings, they may help guide future cell-based therapeutic strategies. This review provides an overview of the current applications, discusses the challenges and limitations, and highlights future avenues of HBCXs in neuroimmunology and translational research.