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REST suppression mediates neural conversion of adult human fibroblasts via microRNA-dependent and -independent pathways

Drouin-Ouellet, Janelle LU ; Lau, Shong LU ; Brattås, Per Ludvik LU ; Ottosson, Daniella LU orcid ; Pircs, Karolina LU orcid ; Grassi, Daniela A LU ; Collins, Lucy M ; Vuono, Romina ; Andersson Sjöland, Annika LU and Westergren-Thorsson, Gunilla LU orcid , et al. (2017) In EMBO Molecular Medicine 9(8). p.1117-1131
Abstract

Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons (iNs), was achieved for the first time 6 years ago. This technology offers a promising shortcut for obtaining patient- and disease-specific neurons for disease modeling, drug screening, and other biomedical applications. However, fibroblasts from adult donors do not reprogram as easily as fetal donors, and no current reprogramming approach is sufficiently efficient to allow the use of this technology using patient-derived material for large-scale applications. Here, we investigate the difference in reprogramming requirements between fetal and adult human fibroblasts and identify REST as a major reprogramming barrier in adult fibroblasts.... (More)

Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons (iNs), was achieved for the first time 6 years ago. This technology offers a promising shortcut for obtaining patient- and disease-specific neurons for disease modeling, drug screening, and other biomedical applications. However, fibroblasts from adult donors do not reprogram as easily as fetal donors, and no current reprogramming approach is sufficiently efficient to allow the use of this technology using patient-derived material for large-scale applications. Here, we investigate the difference in reprogramming requirements between fetal and adult human fibroblasts and identify REST as a major reprogramming barrier in adult fibroblasts. Via functional experiments where we overexpress and knockdown the REST-controlled neuron-specific microRNAs miR-9 and miR-124, we show that the effect of REST inhibition is only partially mediated via microRNA up-regulation. Transcriptional analysis confirmed that REST knockdown activates an overlapping subset of neuronal genes as microRNA overexpression and also a distinct set of neuronal genes that are not activated via microRNA overexpression. Based on this, we developed an optimized one-step method to efficiently reprogram dermal fibroblasts from elderly individuals using a single-vector system and demonstrate that it is possible to obtain iNs of high yield and purity from aged individuals with a range of familial and sporadic neurodegenerative disorders including Parkinson's, Huntington's, as well as Alzheimer's disease.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
EMBO Molecular Medicine
volume
9
issue
8
pages
1117 - 1131
publisher
Wiley-Blackwell
external identifiers
  • scopus:85021313053
  • wos:000406702900010
  • pmid:28646119
ISSN
1757-4684
DOI
10.15252/emmm.201607471
language
English
LU publication?
yes
id
2c199a1b-ab17-48e8-a705-b007551ccbc2
date added to LUP
2017-06-27 13:39:33
date last changed
2024-10-29 09:37:28
@article{2c199a1b-ab17-48e8-a705-b007551ccbc2,
  abstract     = {{<p>Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons (iNs), was achieved for the first time 6 years ago. This technology offers a promising shortcut for obtaining patient- and disease-specific neurons for disease modeling, drug screening, and other biomedical applications. However, fibroblasts from adult donors do not reprogram as easily as fetal donors, and no current reprogramming approach is sufficiently efficient to allow the use of this technology using patient-derived material for large-scale applications. Here, we investigate the difference in reprogramming requirements between fetal and adult human fibroblasts and identify REST as a major reprogramming barrier in adult fibroblasts. Via functional experiments where we overexpress and knockdown the REST-controlled neuron-specific microRNAs miR-9 and miR-124, we show that the effect of REST inhibition is only partially mediated via microRNA up-regulation. Transcriptional analysis confirmed that REST knockdown activates an overlapping subset of neuronal genes as microRNA overexpression and also a distinct set of neuronal genes that are not activated via microRNA overexpression. Based on this, we developed an optimized one-step method to efficiently reprogram dermal fibroblasts from elderly individuals using a single-vector system and demonstrate that it is possible to obtain iNs of high yield and purity from aged individuals with a range of familial and sporadic neurodegenerative disorders including Parkinson's, Huntington's, as well as Alzheimer's disease.</p>}},
  author       = {{Drouin-Ouellet, Janelle and Lau, Shong and Brattås, Per Ludvik and Ottosson, Daniella and Pircs, Karolina and Grassi, Daniela A and Collins, Lucy M and Vuono, Romina and Andersson Sjöland, Annika and Westergren-Thorsson, Gunilla and Graff, Caroline and Minthon, Lennart and Toresson, Håkan and Barker, Roger A and Jakobsson, Johan and Parmar, Malin}},
  issn         = {{1757-4684}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{8}},
  pages        = {{1117--1131}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{EMBO Molecular Medicine}},
  title        = {{REST suppression mediates neural conversion of adult human fibroblasts via microRNA-dependent and -independent pathways}},
  url          = {{http://dx.doi.org/10.15252/emmm.201607471}},
  doi          = {{10.15252/emmm.201607471}},
  volume       = {{9}},
  year         = {{2017}},
}