GSE110952
Functional studies of missense TREM2 mutations in human stem cell-derived microglia
The derivation of microglia from human pluripotent stem cells provides systems for understanding microglial biology and enables functional studies of neurological disease-causing mutations.  We describe a robust method for the derivation and maintenance of microglia from human stem cells, which are phenotypically and functionally comparable to primary human microglia. We used stem cell-derived microglia to study the consequences of missense mutations in the microglial-expressed protein Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which are causal for a frontotemporal dementia-like (FTD-like) syndrome and Nasu-Hakola disease (NHD). While many ligands and functions for TREM2 have been described, it is not known how TREM2 signalling dysregulation affects specific elements of microglial biology to influence disease pathogenesis. We find that mutant TREM2 accumulates in its immature form, does not undergo typical proteolysis, and is not properly trafficked to the plasma membrane of patient-derived microglia. However, in the absence of plasma membrane TREM2, microglia differentiate normally, respond to stimulation with lipopolysaccharide, and are phagocytically competent. These data indicate that dementia-associated TREM2 mutations have subtle effects on microglia biology, consistent with the late adult-onset of disease in individuals with these mutations. Overall design: Primitive macrophage precursors (iPMP) and microglia (iMG) were derived from induced pluripotent human stem cells. Total RNA from each cell type was isolated from three independent differentiations of two genetic backgrounds (AD3-4 and NDC1.2).