Department of Development and Regeneration, Stem Cell Biology and Embryology, KU Leuven Stem Cell Institute, Leuven, Belgium; Laboratory for the Research of Neurodegenerative Diseases, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium.
Department of Development and Regeneration, Stem Cell Biology and Embryology, KU Leuven Stem Cell Institute, Leuven, Belgium.
Alzheimers Dement. 2019 Mar;15(3):453-464. doi: 10.1016/j.jalz.2018.09.006. Epub 2018 Nov 12.
Murine microglia expressing the Alzheimer's disease-linked TREM2 mutation display variable decrease in phagocytosis, while impaired phagocytosis is reported following loss of TREM2. However, no data exist on TREM2 human microglia. Therefore, we created human pluripotent stem cell (hPSC) monocytes and transdifferentiated microglia-like cells (tMGs) to examine the effect of the TREM2 mutation and loss of TREM2 on phagocytosis.
We generated isogenic TREM2, TREM2, and TREM2 hPSCs using CRISPR/Cas9. Following differentiation to monocytes and tMGs, we studied the uptake of Escherichia coli fragments and analyzed amyloid plaque clearance from cryosections of APP/PS1 mouse brains.
We demonstrated that tMGs resemble cultured human microglia. TREM2 and TREM2 hPSC monocytes and tMGs phagocytosed significantly less E. coli fragments and cleared less amyloid plaques than wild-type hPSC progeny, with no difference for TREM2 progeny.
In vitro phagocytosis of hPSC monocytes and tMGs was not affected by the TREM2 mutation but was significantly impaired in TREM2 and TREM2 progeny.
