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Small molecules increase direct neural conversion of human fibroblasts

Pfisterer, Ulrich LU ; Ek, Fredrik LU ; Lang, Stefan LU ; Soneji, Shamit LU ; Olsson, Roger LU and Parmar, Malin LU (2016) In Scientific Reports 6.
Abstract

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... (More)

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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author
organization
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type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
6
publisher
Nature Publishing Group
external identifiers
  • scopus:85003904916
  • wos:000389184000001
ISSN
2045-2322
DOI
10.1038/srep38290
language
English
LU publication?
yes
id
9a630a69-552b-4a9a-9ff6-8b65b39b9eba
date added to LUP
2016-12-23 10:47:26
date last changed
2017-10-22 05:24:11
@article{9a630a69-552b-4a9a-9ff6-8b65b39b9eba,
  abstract     = {<p>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.</p>},
  articleno    = {38290},
  author       = {Pfisterer, Ulrich and Ek, Fredrik and Lang, Stefan and Soneji, Shamit and Olsson, Roger and Parmar, Malin},
  issn         = {2045-2322},
  language     = {eng},
  month        = {12},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Small molecules increase direct neural conversion of human fibroblasts},
  url          = {http://dx.doi.org/10.1038/srep38290},
  volume       = {6},
  year         = {2016},
}