Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro
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The paper generated induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) and exposed them to brain-derived substrates like synaptosomes, myelin debris, apoptotic neurons, and amyloid beta fibrils. Single-cell RNA sequencing of the iMGLs showed that exposure to the substrates induced diverse transcriptional states that mapped to microglial states found in vivo, including a neurodegenerative disease-associated microglia (DAM) state.
The DAM state in iMGLs depended on TREM2 signaling, similar to DAMs in vivo. Integrative analysis showed the iMGL DAM state aligned with DAMs from human cortical biopsies and Alzheimer's disease mouse models. To enable genetic manipulation of iMGLs, the researchers developed a lentiviral transduction method using Vpx to overcome resistance to viral infection. Overexpression of the transcription factor MITF drove an overlapping transcriptional signature with the DAM state and increased phagocytosis, identifying it as a potential regulator of the DAM phenotype.
The iMGL platform and genetic manipulation method provide tools to model and study functional properties of diverse human microglia states relevant to health and neurodegenerative disease.
https://www.nature.com/articles/s41590-023-01558-2
