Human Induced Pluripotent Stem Cell-Derived Microglia-Like Cells Harboring TREM2 Missense Mutations Show Specific Deficits in Phagocytosis.
Human Induced Pluripotent Stem Cell-Derived Microglia-Like Cells Harboring TREM2 Missense Mutations Show Specific Deficits in Phagocytosis.
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DOI：
10.1016/j.celrep.2018.07.094
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发表时间：
2018-08-28
期刊：
影响因子：
8.8
通讯作者：
Pocock JM
中科院分区：
文献类型：
--
作者：
Garcia-Reitboeck P;Phillips A;Piers TM;Villegas-Llerena C;Butler M;Mallach A;Rodrigues C;Arber CE;Heslegrave A;Zetterberg H;Neumann H;Neame S;Houlden H;Hardy J;Pocock JM
小胶质细胞（大脑的免疫细胞）的功能障碍与神经变性有关。TREM 2中的纯合错义突变导致Nasu-Hakola病（NHD），一种早发性痴呆。为了研究这些TREM 2变体的后果，我们从纯合T66 M或W50 C错义突变引起的NHD患者中产生了诱导多能干细胞衍生的小胶质细胞样细胞（iPSC-MGLC）。iPSC-MGLC表达小胶质细胞标志物，并分泌比原代巨噬细胞更高水平的TREM 2。TREM 2表达和分泌在变体系中减少。LPS介导的细胞因子分泌在对照和TREM 2变体iPSC-MGLC之间是相当的，而与对照相比，在含有错义突变的细胞中存活率显著降低。此外，TREM 2错义突变导致凋亡小体的吞噬作用明显受损，但在大肠杆菌或酵母多糖底物中没有。结合凋亡细胞诱导的细胞因子释放和迁移的变化，这些数据鉴定了携带TREM 2错义突变的iPSC-MGLC响应特定致病信号的能力的特定缺陷。从TREM 2 T66 M和W50 C突变携带者产生的人小胶质细胞样细胞杂合和纯合TREM 2变体损害可溶性TREM 2的脱落LPS暴露后TREM 2变体中未改变的细胞因子分泌在TREM 2变体中观察到小胶质细胞功能的底物特异性损害Garcia-Reitboeck et al.描述了从患有由免疫受体基因TREM 2的变体引起的早发性痴呆的患者中产生人诱导多能干细胞衍生的小胶质细胞样细胞。他们观察到TREM 2变体细胞的功能缺陷，包括可溶性TREM 2分泌减少，选择性减少凋亡神经元细胞的吞噬作用，以及迁移能力的缺陷。
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. Generated human microglia-like cells from TREM2 T66M and W50C mutation carriers Heterozygous and homozygous TREM2 variants impair shedding of soluble TREM2 Cytokine secretion not altered in TREM2 variants following LPS exposure Substrate specific impairment of microglial function observed in TREM2 variants Garcia-Reitboeck et al. describe the generation of human induced pluripotent stem cell-derived microglia-like cells from patients with early-onset dementia caused by variants in the immune receptor gene TREM2. They observed functional deficits in TREM2 variant cells, including reduced soluble TREM2 secretion, selectively reduced phagocytosis of apoptotic neuronal cells, and a deficit in migratory capacity.
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影响因子：
3.7
作者：
Hale C;Yeung A;Goulding D;Pickard D;Alasoo K;Powrie F;Dougan G;Mukhopadhyay S
通讯作者：
Mukhopadhyay S
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
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Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
25
作者：
Pandya H;Shen MJ;Ichikawa DM;Sedlock AB;Choi Y;Johnson KR;Kim G;Brown MA;Elkahloun AG;Maric D;Sweeney CL;Gossa S;Malech HL;McGavern DB;Park JK
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Park JK
DOI：
10.1084/jem.20142322
发表时间：
2015-03-09
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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通讯作者：
Lamb BT
影响因子：
4.4
作者：
Hamerman, Jessica A.;Jarjoura, Vessica R.;Lanier, Lewis L.
通讯作者：
Lanier, Lewis L.