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Figure 2. The versatile applications of human pluripotent stem cell-derived microglia. Since MGLs and their derivatives were first developed from hPSCs, they have been applied in a variety of disease model systems in a very short time. To date, the most prominent studies have been conducted in the context of modeling multiple neurodegenerative and neurodevelopmental diseases, omics and systematic analysis, interaction with other CNS cell types, as well as transplantation-based human-mouse chimerism. The most widespread application is the use of monocultured MGLs in dissecting the inflammatory endeavors underlying neurodegenerative diseases. Given the complex interactions between microglia and other CNS cells, hPSC-derived MGLs were further co-cultured with hPSC-derived neurons and astrocytes, or engrafted within hPSC-derived BOs, which largely lack microglia due to their different embryonic origins, to study human microglial functions in either health and disease state closer to brain microglia. Other than incorporating into in vitro cultured BOs, human MGLs can also be transplanted in vivo into a fully developed mammalian brain and largely repopulated and functionally integrated into the brain, producing extensive chimerism. The chimeric model is intended to faithfully study the pathophysiology of human microglia within a mature and intact milieu. Moreover, hPSC-derived MGLs also provide a viable platform for conducting functional genomics or drug screening. For example, a promising approach is enabled by CRISPR-based functional genomics in differentiated MGLs. Pooled CRISPRa and CRISPRi screens enable scalable modeling of changes in gene expression and discovery of regulatory mechanisms through gene screens. In addition, integrative omics analyses, including RNA-seq, ATAC-seq, ChIP-seq, as well as proteomics, have been performed based on this platform. BOs: Brain organoids; CNS: central nervous system; CRISPR: clustered regularly interspaced short palindromic repeats; CRISPRa: CRISPR-activation; CRISPRi: CRISPR interference; hPSC: human pluripotent stem cells; MGLs: microglia-like cells; WT: wild type.