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Small molecules increase direct neural conversion of human fibroblasts

The generation of human induced neurons (hiNs) via exogenous delivery of neural transcription factors represents a novel technique to obtain disease and patient specific neurons. These cells have the potential to be used for disease modeling, diagnostics and drug screening, and also to be further de...

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Autores principales: Pfisterer, Ulrich, Ek, Fredrik, Lang, Stefan, Soneji, Shamit, Olsson, Roger, Parmar, Malin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137010/
https://www.ncbi.nlm.nih.gov/pubmed/27917895
http://dx.doi.org/10.1038/srep38290
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author Pfisterer, Ulrich
Ek, Fredrik
Lang, Stefan
Soneji, Shamit
Olsson, Roger
Parmar, Malin
author_facet Pfisterer, Ulrich
Ek, Fredrik
Lang, Stefan
Soneji, Shamit
Olsson, Roger
Parmar, Malin
author_sort Pfisterer, Ulrich
collection PubMed
description The generation of human induced neurons (hiNs) via exogenous delivery of neural transcription factors represents a novel technique to obtain disease and patient specific neurons. These cells have the potential to be used for disease modeling, diagnostics and drug screening, and also to be further developed for brain repair. In the present study, we utilized hiNs to develop an unbiased screening assay for small molecules that increase the conversion efficiency. Using this assay, we screened 307 compounds from five annotated libraries and identified six compounds that were very potent in potentiating the reprogramming process. When combined in an optimal combination and dose, these compounds increased the reprogramming efficiency of human fibroblasts more than 6-fold. Global gene expression and CellNet analysis at different timepoints during the reprogramming process revealed that neuron-specific genes and gene regulatory networks (GRNs) became progressively more activated while converting cells shut down fibroblast-specific GRNs. Further bioinformatics analysis revealed that the addition of the six compound resulted in the accelerated upregulation of a subset of neuronal genes, and also increased expression of genes associated with transcriptional activity and mediation of cellular stress response.
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spelling pubmed-51370102017-01-27 Small molecules increase direct neural conversion of human fibroblasts Pfisterer, Ulrich Ek, Fredrik Lang, Stefan Soneji, Shamit Olsson, Roger Parmar, Malin Sci Rep Article The generation of human induced neurons (hiNs) via exogenous delivery of neural transcription factors represents a novel technique to obtain disease and patient specific neurons. These cells have the potential to be used for disease modeling, diagnostics and drug screening, and also to be further developed for brain repair. In the present study, we utilized hiNs to develop an unbiased screening assay for small molecules that increase the conversion efficiency. Using this assay, we screened 307 compounds from five annotated libraries and identified six compounds that were very potent in potentiating the reprogramming process. When combined in an optimal combination and dose, these compounds increased the reprogramming efficiency of human fibroblasts more than 6-fold. Global gene expression and CellNet analysis at different timepoints during the reprogramming process revealed that neuron-specific genes and gene regulatory networks (GRNs) became progressively more activated while converting cells shut down fibroblast-specific GRNs. Further bioinformatics analysis revealed that the addition of the six compound resulted in the accelerated upregulation of a subset of neuronal genes, and also increased expression of genes associated with transcriptional activity and mediation of cellular stress response. Nature Publishing Group 2016-12-05 /pmc/articles/PMC5137010/ /pubmed/27917895 http://dx.doi.org/10.1038/srep38290 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Pfisterer, Ulrich
Ek, Fredrik
Lang, Stefan
Soneji, Shamit
Olsson, Roger
Parmar, Malin
Small molecules increase direct neural conversion of human fibroblasts
title Small molecules increase direct neural conversion of human fibroblasts
title_full Small molecules increase direct neural conversion of human fibroblasts
title_fullStr Small molecules increase direct neural conversion of human fibroblasts
title_full_unstemmed Small molecules increase direct neural conversion of human fibroblasts
title_short Small molecules increase direct neural conversion of human fibroblasts
title_sort small molecules increase direct neural conversion of human fibroblasts
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137010/
https://www.ncbi.nlm.nih.gov/pubmed/27917895
http://dx.doi.org/10.1038/srep38290
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