Dissecting microglial contributions to neurodegenerative disease pathophysiology using human pluripotent stem cells

Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss. Microglia, the brain's resident macrophages, are key contributors to disease pathogenesis, with many genetic risk variants enriched in microglia-specific genes. While rodent models have provided valuable insights, human induced pluripotent stem cell (iPSC) and embryonic stem cell (ESC) technologies now enable the generation of human microglia-like cells, offering a physiologically relevant platform to study human microglial biology. This review discusses the developmental origins and functions of microglia, current differentiation approaches, and how these models help elucidate disease-relevant phenotypes and molecular mechanisms in neurodegeneration.