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

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 t...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382323/
https://www.ncbi.nlm.nih.gov/pubmed/37500887
http://dx.doi.org/10.1038/s41590-023-01558-2
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author 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
author_facet 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
author_sort Dolan, Michael-John
collection PubMed
description 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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spelling pubmed-103823232023-07-30 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 Nat Immunol Resource 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. Nature Publishing Group US 2023-07-27 2023 /pmc/articles/PMC10382323/ /pubmed/37500887 http://dx.doi.org/10.1038/s41590-023-01558-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Resource
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
Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro
title Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro
title_full Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro
title_fullStr Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro
title_full_unstemmed Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro
title_short Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro
title_sort exposure of ipsc-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro
topic Resource
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382323/
https://www.ncbi.nlm.nih.gov/pubmed/37500887
http://dx.doi.org/10.1038/s41590-023-01558-2
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