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29.03.18 In vitro model of human microglia derived from patient's stem cells developed in Livesey lab

last modified Mar 29, 2018 05:34 PM
This stem cell model of microglia, the brain’s macrophages, enabled the Livesey lab to examine the effects of mutations in the TREM2 receptor, which are causative for dementia
29.03.18 In vitro model of human microglia derived from patient's stem cells developed in Livesey lab

Stem cell-derived microglia (red) colonise developing neural tissue

Functional studies of missense TREM2 mutations in human stem cell-derived microglia

Brownjohn PW et al. (2018) Stem Cell Reports 

Advanced online publication 29 March, Publication stage: In Press Corrected Proof

DOI: 10.1016/j.stemcr.2018.03.003

 

Highlights from the paper

  • Microglia can be efficiently differentiated from human iPSCs
  • iPSC microglia resemble human primary microglia transcriptionally and functionally
  • Disease-causing mutations in TREM2 affect receptor processing and expression
  • TREM2 mutant microglia differentiate, respond to pathogenic stimuli, and phagocytose

Summary from the paper

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 to 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.

 

Read more about research in the Livesey lab.

 

 

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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Link to full list on PubMed