Translational modelling of human microglia from cultures to chimeras

Microglia play a crucial role in maintaining homeostasis of the central nervous system, whereas their dysfunction is implicated in the pathogenesis of various neurological diseases. Nevertheless, interspecific genetic differences pose challenges to translating findings from conventional rodent models. Human pluripotent stem cell-derived microglia offer a genetically relevant alternative, but these cells undergo profound transcriptomic changes and lose key homeostatic features when isolated from physiological brain cues. Accordingly, research has increasingly focused on advanced modelling platforms designed to restore the microenvironment required for in vivo microglial identity and functionality. This review examines the evolution of human microglial platforms, encompassing foundational generation protocols and multicellular integration. The discussion extends from two-dimensional co-cultures to three-dimensional brain organoids and includes human microglia chimeric models established via xenotransplantation to provide a physiological niche. In summary, the human pluripotent stem cell-based approach represents a valuable experimental pipeline for microglia research, facilitating the investigation of polygenic structures underlying human neurological diseases, from high-throughput screening to in vivo preclinical validation.