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Expression-based drug screening of neural progenitor cells from individuals with schizophrenia

A lack of biologically relevant screening models hinders the discovery of better treatments for schizophrenia (SZ) and other neuropsychiatric disorders. Here we compare the transcriptional responses of 8 commonly used cancer cell lines (CCLs) directly with that of human induced pluripotent stem cell...

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Autores principales: Readhead, Benjamin, Hartley, Brigham J., Eastwood, Brian J., Collier, David A., Evans, David, Farias, Richard, He, Ching, Hoffman, Gabriel, Sklar, Pamela, Dudley, Joel T., Schadt, Eric E., Savić, Radoslav, Brennand, Kristen J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200740/
https://www.ncbi.nlm.nih.gov/pubmed/30356048
http://dx.doi.org/10.1038/s41467-018-06515-4
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author Readhead, Benjamin
Hartley, Brigham J.
Eastwood, Brian J.
Collier, David A.
Evans, David
Farias, Richard
He, Ching
Hoffman, Gabriel
Sklar, Pamela
Dudley, Joel T.
Schadt, Eric E.
Savić, Radoslav
Brennand, Kristen J.
author_facet Readhead, Benjamin
Hartley, Brigham J.
Eastwood, Brian J.
Collier, David A.
Evans, David
Farias, Richard
He, Ching
Hoffman, Gabriel
Sklar, Pamela
Dudley, Joel T.
Schadt, Eric E.
Savić, Radoslav
Brennand, Kristen J.
author_sort Readhead, Benjamin
collection PubMed
description A lack of biologically relevant screening models hinders the discovery of better treatments for schizophrenia (SZ) and other neuropsychiatric disorders. Here we compare the transcriptional responses of 8 commonly used cancer cell lines (CCLs) directly with that of human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) from 12 individuals with SZ and 12 controls across 135 drugs, generating 4320 unique drug-response transcriptional signatures. We identify those drugs that reverse post-mortem SZ-associated transcriptomic signatures, several of which also differentially regulate neuropsychiatric disease-associated genes in a cell type (hiPSC NPC vs. CCL) and/or a diagnosis (SZ vs. control)-dependent manner. Overall, we describe a proof-of-concept application of transcriptomic drug screening to hiPSC-based models, demonstrating that the drug-induced gene expression differences observed with patient-derived hiPSC NPCs are enriched for SZ biology, thereby revealing a major advantage of incorporating cell type and patient-specific platforms in drug discovery.
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spelling pubmed-62007402018-10-26 Expression-based drug screening of neural progenitor cells from individuals with schizophrenia Readhead, Benjamin Hartley, Brigham J. Eastwood, Brian J. Collier, David A. Evans, David Farias, Richard He, Ching Hoffman, Gabriel Sklar, Pamela Dudley, Joel T. Schadt, Eric E. Savić, Radoslav Brennand, Kristen J. Nat Commun Article A lack of biologically relevant screening models hinders the discovery of better treatments for schizophrenia (SZ) and other neuropsychiatric disorders. Here we compare the transcriptional responses of 8 commonly used cancer cell lines (CCLs) directly with that of human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) from 12 individuals with SZ and 12 controls across 135 drugs, generating 4320 unique drug-response transcriptional signatures. We identify those drugs that reverse post-mortem SZ-associated transcriptomic signatures, several of which also differentially regulate neuropsychiatric disease-associated genes in a cell type (hiPSC NPC vs. CCL) and/or a diagnosis (SZ vs. control)-dependent manner. Overall, we describe a proof-of-concept application of transcriptomic drug screening to hiPSC-based models, demonstrating that the drug-induced gene expression differences observed with patient-derived hiPSC NPCs are enriched for SZ biology, thereby revealing a major advantage of incorporating cell type and patient-specific platforms in drug discovery. Nature Publishing Group UK 2018-10-24 /pmc/articles/PMC6200740/ /pubmed/30356048 http://dx.doi.org/10.1038/s41467-018-06515-4 Text en © The Author(s) 2018 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/.
spellingShingle Article
Readhead, Benjamin
Hartley, Brigham J.
Eastwood, Brian J.
Collier, David A.
Evans, David
Farias, Richard
He, Ching
Hoffman, Gabriel
Sklar, Pamela
Dudley, Joel T.
Schadt, Eric E.
Savić, Radoslav
Brennand, Kristen J.
Expression-based drug screening of neural progenitor cells from individuals with schizophrenia
title Expression-based drug screening of neural progenitor cells from individuals with schizophrenia
title_full Expression-based drug screening of neural progenitor cells from individuals with schizophrenia
title_fullStr Expression-based drug screening of neural progenitor cells from individuals with schizophrenia
title_full_unstemmed Expression-based drug screening of neural progenitor cells from individuals with schizophrenia
title_short Expression-based drug screening of neural progenitor cells from individuals with schizophrenia
title_sort expression-based drug screening of neural progenitor cells from individuals with schizophrenia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200740/
https://www.ncbi.nlm.nih.gov/pubmed/30356048
http://dx.doi.org/10.1038/s41467-018-06515-4
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