Advancements in 3D models for studying human iPSC-microglia: Insights into neurodevelopment and neurological disorders

Microglia are immune cells of the central nervous system, playing a vital role in brain development, homeostasis, and disease. When these cells become dysfunctional, they can contribute to various psychiatric disorders and neurodegenerative diseases. To enhance our understanding of microglial function, researchers are increasingly employing human cell-based models. This approach significantly improves our investigations into these complex conditions and aids in ongoing drug development efforts. In vitro models of human microglia, derived from disease-specific induced pluripotent stem cells (iPSCs), are essential for examining their roles in neurological disorders. These models provide a controlled environment for studying the cellular and molecular processes involved in microglia-driven neuroinflammation and neurodegeneration. Integrating microglia into three-dimensional (3D) organoid cultures yields a more physiologically relevant model of the human brain, thereby advancing the study of brain development and the pathology of neurological disorders. Currently, brain organoid models are limited by the absence of key components, such as vasculature, which restricts their growth and hinders the optimal modeling of neurodevelopment, as well as the examination of microglial forms and functions. This review explores newly developed 3D models for generating human-induced microglia and investigates the potential of these in vitro systems to improve our understanding of brain development and the disorders that emerge from its disruption. • Human microglia play a crucial role in neurodevelopment and is implicated in various neurological disorders. • Human induced pluripotent stem cell (iPSC)-derived microglia (iMicro) provide an in vitro platform to study human microglia functions. • The coculture of iMicro with neural tissues, enables the study of human microglial functions within their microenvironment.