Human induced pluripotent stem cell-derived microglia-like cells harboring TREM2 missense mutations show specific deficits in phagocytosis
Author(s)
Type
Journal Article
Abstract
Dysfunction of microglia, the brain’s immune cells, is linked to neurodegeneration. Homozygous missense mutations in TREM2 cause Nasu-Hakola disease (NHD), an early-onset dementia. To study the consequences of these TREM2 variants, we generated induced pluripotent stem cell-derived microglia-like cells (iPSC-MGLCs) from patients with NHD caused by homozygous T66M or W50C missense mutations. iPSC-MGLCs expressed microglial markers and secreted higher levels of TREM2 than primary macrophages. TREM2 expression and secretion were reduced in variant lines. LPS-mediated cytokine secretion was comparable between control and TREM2 variant iPSC-MGLCs, whereas survival was markedly reduced in cells harboring missense mutations when compared with controls. Furthermore, TREM2 missense mutations caused a marked impairment in the phagocytosis of apoptotic bodies, but not in Escherichia coli or zymosan substrates. Coupled with changes in apoptotic cell-induced cytokine release and migration, these data identify specific deficits in the ability of iPSC-MGLCs harboring TREM2 missense mutations to respond to specific pathogenic signals.
Date Issued
2018-08
Date Acceptance
2018-07-27
Citation
Cell Reports, 2018, 24 (9), pp.2300-2311
ISSN
2211-1247
Publisher
Elsevier BV
Start Page
2300
End Page
2311
Journal / Book Title
Cell Reports
Volume
24
Issue
9
Copyright Statement
© 2018 The Author(s).
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Identifier
https://www.sciencedirect.com/science/article/pii/S2211124718312270?via%3Dihub
Subjects
0601 Biochemistry and Cell Biology
Publication Status
Published
Date Publish Online
2018-08-28