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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, Sasa; 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.
Afiliação
  • Dolan MJ; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Therrien M; Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA, USA.
  • Jereb S; Harvard Medical School, Boston, MA, USA.
  • Kamath T; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gazestani V; Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA, USA.
  • Atkeson T; Harvard Medical School, Boston, MA, USA.
  • Marsh SE; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Goeva A; Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA, USA.
  • Lojek NM; Harvard Medical School, Boston, MA, USA.
  • Murphy S; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • White CM; Harvard Medical School, Boston, MA, USA.
  • Joung J; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Liu B; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Limone F; Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA, USA.
  • Eggan K; Harvard Medical School, Boston, MA, USA.
  • Hacohen N; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bernstein BE; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Glass CK; Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA, USA.
  • Leinonen V; Broad Institute of MIT and Harvard Cambridge, Cambridge, MA, USA.
  • Blurton-Jones M; Broad Institute of MIT and Harvard Cambridge, Cambridge, MA, USA.
  • Zhang F; Department of Biological Engineering, MIT, Cambridge, MA, USA.
  • Epstein CB; Howard Hughes Medical Institute, Boston, MA, USA.
  • Macosko EZ; Department of Brain and Cognitive Science, MIT, Cambridge, MA, USA.
  • Stevens B; McGovern Institute for Brain Research at MIT, Cambridge, MA, USA.
Nat Immunol ; 24(8): 1382-1390, 2023 08.
Article em En | MEDLINE | ID: mdl-37500887
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doenças Neurodegenerativas / Células-Tronco Pluripotentes Induzidas / Doença de Alzheimer Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doenças Neurodegenerativas / Células-Tronco Pluripotentes Induzidas / Doença de Alzheimer Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article