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Publications

Journal Article Preprint Epublish 6 citations

PubMed: 38826204 DOI: 10.1101/2024.05.24.595814

A microglia-containing cerebral organoid model to study early life immune challenges.

bioRxiv

Authors: Alice Buonfiglioli, Raphael Kübler, Roy Missall, Renske De Jong, Stephanie Chan, Verena Haage, Stefan Wendt, Ada J Lin, Daniele Mattei, Mara Graziani, Brooke Latour, Frederieke Gigase, Haakon B Nygaard, Philip L De Jager, Lot D De Witte

Affiliations

  • Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Department of Human Genetics, Radboud UMC, Nijmegen, The Netherlands.
  • Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
  • Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, V6T 1Z3, Canada.
  • Division of Neurology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, V6T 1Z3, Canada.
  • Donders Institute for Brain, Cognition and Behaviour, 6500 HB, Nijmegen, The Netherlands.
  • Department of Psychiatry, Radboud UMC, Nijmegen, The Netherlands.

Abstract

Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.

MeSH

Interferon-Gamma, Microglia, Cells, Brain, Neurodevelopmental Disorders, Organoids, Immune System, Neurodevelopment