. Human Induced Pluripotent Stem Cell-Derived Microglia-Like Cells Harboring TREM2 Missense Mutations Show Specific Deficits in Phagocytosis. Cell Rep. 2018 Aug 28;24(9):2300-2311. PubMed.


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  1. Recent advances in the methodology of deriving macrophages and microglia-like cells from induced pluripotent stem cells (iPSCs) has opened up new opportunities to functionally characterize the effects of disease-associated variants (e.g. TREM2, CD33 …) using a "human model system" (Muffat et al., 2016; Abud et al., 2017; Pandya et al., 2017; Douvaras et al., 2017; Haenseler et al., 2017). These iPSC-derived microglia collectively express a set of previously identified microglia signature genes (Butovsky et al., 2014). Nevertheless, iPSC-derived microglia grown in two-dimensional monocultures still show substantial differences to in vivo microglia with respect to gene signature and morphology, and it is clear that microglia change dramatically when cultured or taken out of their natural environment (Gosselin et al., 2017; Bohlen et al., 2017; Jun 2017 news). Approaches to grow these cells in co-culture with neurons or even in three dimensions using cortical organoids has been shown to move them another step closer to microglia in vivo (Haenseler et al., 2017; Abud et al., 2017; Brownjohn et al., 2018). 

    The study by Reitboeck and colleagues follows up recently published work by Livesey and colleagues in characterizing the effect of TREM2 missense mutations causing rare neurodegenerative diseases such as Nasu-Hakola disease (NHD) or frontotemporal-like dementia. Using a protocol initially established by the Cowley lab (Haenseler et al., 2017; van Wilgenburg et al., 2013). Reitboeck and colleagues demonstrate that NHD-associated missense mutations result in misprocessing of TREM2 largely confirming previous results obtained by many labs, including ours, where traditional cell culture models (Kleinberger et al., 2014; Park et al., 2014), primary cells (Kleinberger et al. 2014; Kleinberger et al., 2017), CRISPR/Cas9 generated knock-in mice (Kleinberger et al., 2017) and iPSC-derived microglia have been used (Brownjohn et al. 2018). Furthermore, the presented study largely supports our previous finding that TREM2 is critically involved in regulating the migratory capacity of microglia and microglia-like cells (Mazaheri et al., 2017). Somehow surprising, the authors identify an effect on TREM2 mRNA expression, which has not been observed before. Whether this is a direct effect of the TREM2 variants on mRNA stability or a reduced maturation-efficiency of iPSC-microglia from TREM2 variant carriers remains speculative.

    While we and others have observed a Trem2-dependent effect on the uptake of E.coli particles in models exogenously expressing TREM2 or in bone-marrow-derived macrophages (N'Diaye et al., 2009; Kleinberger et al., 2014; Kleinberger et al., 2017), it is interesting to see that in iPSC-derived microglia TREM2 shows substrate specificity to apoptotic cells, which largely agrees with a previous identified interaction of TREM2 with phospholipids (e.g. phosphatidylserine; Wang et al., 2015). In vivo injection of apoptotic neurons has previously also been shown to change the molecular signature of microglia to a neurodegenerative or disease-associated signature (Krasemann et al., 2017). In line with the substrate specificity observed in this study, microglia of Trem2 knockout mice do not respond properly to injection of apoptotic neurons as shown by reduced migration (Mazaheri et al., 2017). The lack of a TREM2-dependent effect on the phagocytosis of zymosan is less surprising, as zymosan particles have been previously shown not to interact with Trem2 (N'Diaye et al., 2009). Furthermore, stimulation of Dectin-1 (also known as Clec7a) with zymosan was able to rescue metabolic deficits of Trem2 knockout bone-marrow-derived macrophages, indicating that Trem2 is not required for engaging with zymosan particles.

    One limitation of the current human microglia models is highlighted by the observation that iPSC-derived microglia cultured in two dimensions do not show an altered response to inflammatory stimuli, such as treatment with lipopolysaccharide (LPS). As in vivo treatment of a TREM2 knock-in mouse model clearly revealed an exaggerated cytokine response to LPS stimulation (Kleinberger et al., 2017), it will be interesting to study the responses of TREM2 deficient iPSC-derived microglia using co-culture or three-dimensional paradigms.

    Overall, it is very reassuring that the main TREM2-mutation-dependent cell biological phenotypes, identified in much simpler cell culture systems (e.g., HEK293) are completely recapitulated in iPSC-derived microglia from patients harboring NHD-associated TREM2 variants. While keeping the current limitations of iPSC-derived microglia in mind, the presented human model is certainly highly valuable to further delineate the functions of TREM2 and potentially could serve as a model to study TREM2-directed treatment strategies. However, one also needs to be realistic. iPSC-derived human brain cells may be fantastic models for specific questions, which can only be addressed in cells that are affected during the disease. Nevertheless, the gain of novel knowledge concerning the cellular mechanisms of prominent disease-causing mutations/variants in genes such as TREM2, presenilin, or APP remains limited, and basically all major findings were made years before using traditional and much simpler cell culture systems.


    . Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med. 2016 Nov;22(11):1358-1367. Epub 2016 Sep 26 PubMed.

    . iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases. Neuron. 2017 Apr 19;94(2):278-293.e9. PubMed.

    . Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat Neurosci. 2017 May;20(5):753-759. Epub 2017 Mar 2 PubMed.

    . Directed Differentiation of Human Pluripotent Stem Cells to Microglia. Stem Cell Reports. 2017 Jun 6;8(6):1516-1524. Epub 2017 May 18 PubMed.

    . A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response. Stem Cell Reports. 2017 Jun 6;8(6):1727-1742. PubMed.

    . Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci. 2014 Jan;17(1):131-43. Epub 2013 Dec 8 PubMed.

    . An environment-dependent transcriptional network specifies human microglia identity. Science. 2017 Jun 23;356(6344) Epub 2017 May 25 PubMed.

    . Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures. Neuron. 2017 May 17;94(4):759-773.e8. PubMed.

    . Functional Studies of Missense TREM2 Mutations in Human Stem Cell-Derived Microglia. Stem Cell Reports. 2018 Apr 10;10(4):1294-1307. Epub 2018 Mar 29 PubMed.

    . Efficient, long term production of monocyte-derived macrophages from human pluripotent stem cells under partly-defined and fully-defined conditions. PLoS One. 2013;8(8):e71098. Epub 2013 Aug 12 PubMed.

    . TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014 Jul 2;6(243):243ra86. PubMed.

    . Triggering receptor expressed on myeloid cells 2 (TREM2) promotes adipogenesis and diet-induced obesity. Diabetes. 2015 Jan;64(1):117-27. Epub 2014 Aug 11 PubMed.

    . The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 2017 Jul 3;36(13):1837-1853. Epub 2017 May 30 PubMed.

    . TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep. 2017 Jul;18(7):1186-1198. Epub 2017 May 8 PubMed.

    . TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria. J Cell Biol. 2009 Jan 26;184(2):215-23. PubMed.

    . TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell. 2015 Mar 12;160(6):1061-71. Epub 2015 Feb 26 PubMed.

    . The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017 Sep 19;47(3):566-581.e9. PubMed.

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