Microglia Increase Inflammatory Responses in iPSC-Derived Human BrainSpheres

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2018
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Monteiro Abreu, Celina
Gama, Lucio
Krasemann, Susanne
Chesnut, Megan
Odwin-DaCosta, Shelly
Hogberg, Helena T.
Pamies, David
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Frontiers in Microbiology. 2018, 9, 2766. eISSN 1664-302X. Available under: doi: 10.3389/fmicb.2018.02766
Zusammenfassung

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 (mBS). 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-1b, with maximum expression at 6–12 h post-exposure. Increased expression of the IL- 6, IL-1b, tumor necrosis factor alpha (TNF-a), and chemokine (C-C motif) ligand 2 (CCL2) genes was observed in mBS 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)1, our findings suggest that the mBS model is more physiologically relevant and has potential applications in infectious disease and host-pathogen interactions research.

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570 Biowissenschaften, Biologie
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zika virus, organoids, microglial cells, in vitro culture, BrainSpheres
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ISO 690MONTEIRO ABREU, Celina, Lucio GAMA, Susanne KRASEMANN, Megan CHESNUT, Shelly ODWIN-DACOSTA, Helena T. HOGBERG, Thomas HARTUNG, David PAMIES, 2018. Microglia Increase Inflammatory Responses in iPSC-Derived Human BrainSpheres. In: Frontiers in Microbiology. 2018, 9, 2766. eISSN 1664-302X. Available under: doi: 10.3389/fmicb.2018.02766
BibTex
@article{MonteiroAbreu2018-12-04Micro-44724,
  year={2018},
  doi={10.3389/fmicb.2018.02766},
  title={Microglia Increase Inflammatory Responses in iPSC-Derived Human BrainSpheres},
  volume={9},
  journal={Frontiers in Microbiology},
  author={Monteiro Abreu, Celina and Gama, Lucio and Krasemann, Susanne and Chesnut, Megan and Odwin-DaCosta, Shelly and Hogberg, Helena T. and Hartung, Thomas and Pamies, David},
  note={Article Number: 2766}
}
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