iPSC-derived microglia: Decoding roles and therapeutic opportunities in neurodegenerative diseases

Microglia originate from erythro-myeloid progenitors (EMPs) in the early embryonic yolk sac and migrate into the developing brain, where they differentiate and mature under the regulation of chemokines, cytokines, and growth factors. As resident immune cells in the central nervous system (CNS), microglia maintain neural homeostasis by sensing the microenvironment, clearing pathogens, phagocytosing cellular debris, and modulating neuroinflammation and tissue repair. In response to injury or pathological stimuli, microglia adopt diverse activation states and contribute to synaptic remodeling, neuroimmune signaling, and neuroplasticity. Their pronounced functional heterogeneity during normal neurodevelopment and across diverse neurological disorders underscores the need for robust in vitro models. Human induced pluripotent stem cells (hiPSCs)-derived microglia have emerged as a powerful platform to investigate microglial development, neuroinflammatory responses, and microglia-mediated neurodegeneration. This review summarizes current hiPSCs-to-microglia differentiation strategies, highlighting their advantages, limitations, and applications. We further discuss the application of hiPSCs-derived microglia in modeling neurodegenerative diseases and critically evaluate the opportunities and challenges associated with beneficially modulating microglial function in the contexts of microglial depletion and replacement therapies. • Human iPSC-derived microglia provide a robust and versatile platform for dissecting microglial development, heterogeneity, and disease-associated dysfunction across neurodegenerative disorders. This review systematically compares current differentiation strategies and summarizes how iPSC-microglia models recapitulate key pathological mechanisms in ALS, Alzheimer’s disease, Parkinson’s disease, and related conditions. We further critically evaluate emerging therapeutic opportunities and challenges in microglial depletion, replacement, and functional modulation, outlining future directions for microglia-targeted interventions.