Expression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids

Bilal Cakir, Yoshiaki Tanaka, Ferdi Ridvan Kiral, Yangfei Xiang, Onur Dagliyan, Juan Wang, Maria Lee, Allison M. Greaney, Woo Sub Yang, Catherine duBoulay, Mehmet Hamdi Kural, Benjamin Patterson, Mei Zhong, Jonghun Kim, Yalai Bai, Wang Min, Laura E. Niklason, Prabir Patra and In-Hyun Park ()
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Bilal Cakir: Yale School of Medicine
Yoshiaki Tanaka: Yale School of Medicine
Ferdi Ridvan Kiral: Yale School of Medicine
Yangfei Xiang: Yale School of Medicine
Onur Dagliyan: Harvard Medical School
Juan Wang: Yale School of Medicine
Maria Lee: Yale University
Allison M. Greaney: Yale University
Woo Sub Yang: Yale School of Medicine
Catherine duBoulay: Colby College
Mehmet Hamdi Kural: Yale School of Medicine
Benjamin Patterson: Yale School of Medicine
Mei Zhong: Yale School of Medicine
Jonghun Kim: Yale School of Medicine
Yalai Bai: Yale School of Medicine
Wang Min: Yale School of Medicine
Laura E. Niklason: Yale School of Medicine
Prabir Patra: Yale School of Medicine
In-Hyun Park: Yale School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Microglia play a role in the emergence and preservation of a healthy brain microenvironment. Dysfunction of microglia has been associated with neurodevelopmental and neurodegenerative disorders. Investigating the function of human microglia in health and disease has been challenging due to the limited models of the human brain available. Here, we develop a method to generate functional microglia in human cortical organoids (hCOs) from human embryonic stem cells (hESCs). We apply this system to study the role of microglia during inflammation induced by amyloid-β (Aβ). The overexpression of the myeloid-specific transcription factor PU.1 generates microglia-like cells in hCOs, producing mhCOs (microglia-containing hCOs), that we engraft in the mouse brain. Single-cell transcriptomics reveals that mhCOs acquire a microglia cell cluster with an intact complement and chemokine system. Functionally, microglia in mhCOs protect parenchyma from cellular and molecular damage caused by Aβ. Furthermore, in mhCOs, we observed reduced expression of Aβ-induced expression of genes associated with apoptosis, ferroptosis, and Alzheimer’s disease (AD) stage III. Finally, we assess the function of AD-associated genes highly expressed in microglia in response to Aβ using pooled CRISPRi coupled with single-cell RNA sequencing in mhCOs. In summary, we provide a protocol to generate mhCOs that can be used in fundamental and translational studies as a model to investigate the role of microglia in neurodevelopmental and neurodegenerative disorders.

Date: 2022
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DOI: 10.1038/s41467-022-28043-y

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