TY - JOUR
T1 - Functional Studies of Missense TREM2 Mutations in Human Stem Cell-Derived Microglia
AU - Brownjohn, Philip W.
AU - Smith, James
AU - Solanki, Ravi
AU - Lohmann, Ebba
AU - Houlden, Henry
AU - Hardy, John
AU - Dietmann, Sabine
AU - Livesey, Frederick J.
N1 - Funding Information:
This research was supported by the Alzheimer's Research UK Stem Cell Research Centre, funded by the Alborada Trust (to P.W.B., J.S., and F.J.L.), a Wellcome Trust Senior Investigator Award (to F.J.L.), and Dementias Platform UK. J.S. was funded by the IMI StemBANCC. R.S. is supported by the University of Cambridge MB/PhD program. Research in F.J.L.'s group benefits from core support to the Gurdon Institute from the Wellcome Trust and Cancer Research UK. We thank patients and their family members for donation of fibroblasts, Dr Vickie Stubbs and Ellie Tuck of the Livesey lab for technical advice, and Kay Harnish of the Gurdon Institute for preparation of cDNA libraries.
Funding Information:
This research was supported by the Alzheimer's Research UK Stem Cell Research Centre , funded by the Alborada Trust (to P.W.B., J.S., and F.J.L.), a Wellcome Trust Senior Investigator Award (to F.J.L.), and Dementias Platform UK . J.S. was funded by the IMI StemBANCC . R.S. is supported by the University of Cambridge MB/PhD program. Research in F.J.L.'s group benefits from core support to the Gurdon Institute from the Wellcome Trust and Cancer Research UK . We thank patients and their family members for donation of fibroblasts, Dr Vickie Stubbs and Ellie Tuck of the Livesey lab for technical advice, and Kay Harnish of the Gurdon Institute for preparation of cDNA libraries.
Publisher Copyright:
© 2018 The Authors
PY - 2018/4/10
Y1 - 2018/4/10
N2 - 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.
AB - 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.
KW - Nasu-Hakola disease
KW - TREM2
KW - dementia
KW - frontotemporal dementia
KW - iPSC-microglia
KW - microglia
KW - neuroinflammation
UR - http://www.scopus.com/inward/record.url?scp=85044341957&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2018.03.003
DO - 10.1016/j.stemcr.2018.03.003
M3 - Article
C2 - 29606617
AN - SCOPUS:85044341957
SN - 2213-6711
VL - 10
SP - 1294
EP - 1307
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 4
ER -