Functional Studies of Missense TREM2 Mutations in Human Stem Cell-Derived Microglia

Philip W. Brownjohn, James Smith, Ravi Solanki, Ebba Lohmann, Henry Houlden, John Hardy, Sabine Dietmann, Frederick J. Livesey

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

Abstract

The derivation of microglia from human stem cells provides systems for understanding microglial biology and enables functional studies of disease-causing mutations. We describe a robust method for the derivation of human microglia from stem cells, which are phenotypically and functionally comparable with primary 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 frontotemporal dementia-like syndrome and Nasu-Hakola disease. We find that mutant TREM2 accumulates in its immature form, does not undergo typical proteolysis, and is not trafficked to the plasma membrane. 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 adult onset of disease in individuals with these mutations. Brownjohn and colleagues report methods to generate microglia from induced pluripotent human stem cells, which they demonstrate are highly similar to cultured primary human microglia. Microglia differentiated from patient-derived stem cells carrying neurological disease-causing mutations in the TREM2 receptor differentiate normally and respond appropriately to pathogenic stimuli, despite the absence of functional TREM2 receptor on the plasma membrane.

Original languageEnglish
Pages (from-to)1294-1307
Number of pages14
JournalStem Cell Reports
Volume10
Issue number4
DOIs
StatePublished - Apr 10 2018

Keywords

  • Nasu-Hakola disease
  • TREM2
  • dementia
  • frontotemporal dementia
  • iPSC-microglia
  • microglia
  • neuroinflammation

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