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Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro

Dolan, Michael-John, Therrien, Martine, Jereb, Saša, Kamath, Tushar, Gazestani, Vahid, Atkeson, Trevor, Marsh, Samuel E., Goeva, Aleksandrina, Lojek, Neal M., Murphy, Sarah, White, Cassandra M., Joung, Julia, Liu, Bingxu, Limone, Francesco, Eggan, Kevin, Hacohen, Nir, Bernstein, Bradley E., Glass, Christopher K., Leinonen, Ville, Blurton-Jones, Mathew, Zhang, Feng, Epstein, Charles B., Macosko, Evan Z., Stevens, Beth·2023·Nature Immunology
DOI 10.1038/s41590-023-01558-2PMC PMC10382323

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Abstract

Microglia, the macrophages of the brain parenchyma, are key players in neurodegenerative diseases such as Alzheimer’s disease. These cells adopt distinct transcriptional subtypes known as states. Understanding state function, especially in human microglia, has been elusive owing to a lack of tools to model and manipulate these cells. Here, we developed a platform for modeling human microglia transcriptional states in vitro. We found that exposure of human stem-cell-differentiated microglia to synaptosomes, myelin debris, apoptotic neurons or synthetic amyloid-beta fibrils generated transcriptional diversity that mapped to gene signatures identified in human brain microglia, including disease-associated microglia, a state enriched in neurodegenerative diseases. Using a new lentiviral approach, we demonstrated that the transcription factor MITF drives a disease-associated transcriptional signature and a highly phagocytic state. Together, these tools enable the manipulation and functional interrogation of human microglial states in both homeostatic and disease-relevant contexts.

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Metadata

Authors
Dolan, M.-J., Therrien, M., Jereb, S., Kamath, T., Gazestani, V., Atkeson, T., Marsh, S. E., Goeva, A., Lojek, N. M., Murphy, S., White, C. M., Joung, J., Liu, B., Limone, F., Eggan, K., Hacohen, N., Bernstein, B. E., Glass, C. K., Leinonen, V., Blurton-Jones, M., Zhang, F., Epstein, C. B., Macosko, E. Z., & Stevens, B.
ORCID
Venue
Nature Immunology
Publisher
Springer Science and Business Media LLC
Published
2023-07-27
Volume
24
Issue
8
Pages
1382-1390
ISSN
  • 1529-2908
  • 1529-2916
DOI
10.1038/s41590-023-01558-2
PMC
PMC10382323
Cited by
185
References
32
Language
en
Licence
Funders
  • Alzheimer’s Association (ADSF-21-831114-C)
  • Life Sciences Research Foundation
  • Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre

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