Dataset Information

IPSC-Derived Human Microglia-like Cells to Study Neurological Diseases.

ABSTRACT: Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates. iMGLs were used to examine the effects of A? fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo. Together, these findings demonstrate that iMGLs can be used to study microglial function, providing important new insight into human neurological disease.

SUBMITTER: Abud EM

PROVIDER: S-EPMC5482419 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases.

Abud Edsel M EM Ramirez Ricardo N RN Martinez Eric S ES Healy Luke M LM Nguyen Cecilia H H CHH Newman Sean A SA Yeromin Andriy V AV Scarfone Vanessa M VM Marsh Samuel E SE Fimbres Cristhian C Caraway Chad A CA Fote Gianna M GM Madany Abdullah M AM Agrawal Anshu A Kayed Rakez R Gylys Karen H KH Cahalan Michael D MD Cummings Brian J BJ Antel Jack P JP Mortazavi Ali A Carson Monica J MJ Poon Wayne W WW Blurton-Jones Mathew M

Neuron 20170401 2

Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they ...[more]

PMID: 28426964

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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

IPSC-Derived Human Microglia-like Cells to Study Neurological Diseases.

Publications

iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases.

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