Dataset Information

PSEN1?E9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia.

ABSTRACT: Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1?E9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca²⁺ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1?E9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.

SUBMITTER: Konttinen H

PROVIDER: S-EPMC6829767 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia.

Konttinen Henna H Cabral-da-Silva Mauricio E Castro MEC Ohtonen Sohvi S Wojciechowski Sara S Shakirzyanova Anastasia A Caligola Simone S Giugno Rosalba R Ishchenko Yevheniia Y Hernández Damián D Fazaludeen Mohammad Feroze MF Eamen Shaila S Budia Mireia Gómez MG Fagerlund Ilkka I Scoyni Flavia F Korhonen Paula P Huber Nadine N Haapasalo Annakaisa A Hewitt Alex W AW Vickers James J Smith Grady C GC Oksanen Minna M Graff Caroline C Kanninen Katja M KM Lehtonen Sarka S Propson Nicholas N Schwartz Michael P MP Pébay Alice A Koistinaho Jari J Ooi Lezanne L Malm Tarja T

Stem cell reports 20190912 4

Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with ...[more]

PMID: 31522977

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Project description:Human induced pluripotent stem cells (iPSCs), together with 21st century cell culture methods, have the potential to better model human physiology with applications in toxicology, disease modeling, and the study of host-pathogen interactions. Several models of the human brain have been developed recently, demonstrating cell-cell interactions of multiple cell types with physiologically relevant 3D structures. Most current models, however, lack the ability to represent the inflammatory response in the brain because they do not include a microglial cell population. Microglia, the resident immunocompetent phagocytes in the central nervous system (CNS), are not only important in the inflammatory response and pathogenesis; they also function in normal brain development, strengthen neuronal connections through synaptic pruning, and are involved in oligodendrocyte and neuronal survival. Here, we have successfully introduced a population of human microglia into 3D human iPSC-derived brain spheres (BrainSpheres, BS) through co-culturing cells of the Immortalized Human Microglia - SV40 cell line with the BS model (?BS). We detected an inflammatory response to lipopolysaccharides (LPS) and flavivirus infection, which was only elicited in the model when microglial cells were present. A concentration of 20 ng/mL of LPS increased gene expression of the inflammatory cytokines interleukin-6 (IL-6), IL-10, and IL-1?, with maximum expression at 6-12 h post-exposure. Increased expression of the IL-6, IL-1?, tumor necrosis factor alpha (TNF-?), and chemokine (C-C motif) ligand 2 (CCL2) genes was observed in ?BS following infection with Zika and Dengue Virus, suggesting a stronger inflammatory response in the model when microglia were present than when only astrocyte, oligodendrocyte, and neuronal populations were represented. Microglia innately develop within cerebral organoids (Nature communications), our findings suggest that the ?BS model is more physiologically relevant and has potential applications in infectious disease and host-pathogen interactions research.

Dataset Information

PSEN1?E9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia.

Publications

PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia.

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