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dc.contributor.authorDrouin-Ouellet, Janelle
dc.contributor.authorLau, Shong
dc.contributor.authorBrattås, Per Ludvik
dc.contributor.authorRylander Ottosson, Daniella
dc.contributor.authorPircs, Karolina
dc.contributor.authorGrassi, Daniela A
dc.contributor.authorCollins, Lucy M
dc.contributor.authorVuono, Romina
dc.contributor.authorAndersson Sjöland, Annika
dc.contributor.authorWestergren-Thorsson, Gunilla
dc.contributor.authorGraff, Caroline
dc.contributor.authorMinthon, Lennart
dc.contributor.authorToresson, Håkan
dc.contributor.authorBarker, Roger A
dc.contributor.authorJakobsson, Johan
dc.contributor.authorParmar, Malin
dc.date.accessioned2017-11-27T14:07:05Z
dc.date.available2017-11-27T14:07:05Z
dc.date.issued2017-08
dc.identifier.issn1757-4676
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/269725
dc.description.abstractDirect 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.
dc.format.mediumPrint
dc.languageeng
dc.publisherEMBO
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectNeurons
dc.subjectFibroblasts
dc.subjectHumans
dc.subjectRepressor Proteins
dc.subjectMicroRNAs
dc.subjectCytological Techniques
dc.subjectGene Expression Profiling
dc.subjectAdult
dc.subjectCell Transdifferentiation
dc.subjectGene Knockdown Techniques
dc.titleREST suppression mediates neural conversion of adult human fibroblasts via microRNA-dependent and -independent pathways.
dc.typeArticle
prism.endingPage1131
prism.issueIdentifier8
prism.publicationDate2017
prism.publicationNameEMBO Mol Med
prism.startingPage1117
prism.volume9
dc.identifier.doi10.17863/CAM.16664
rioxxterms.versionofrecord10.15252/emmm.201607471
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-08
dc.contributor.orcidJakobsson, Johan [0000-0003-0669-7673]
dc.contributor.orcidParmar, Malin [0000-0001-5002-4199]
dc.identifier.eissn1757-4684
rioxxterms.typeJournal Article/Review
pubs.funder-project-idLund University
pubs.funder-project-idMedical Research Council (MC_PC_12009)
pubs.funder-project-idEuropean Commission (602278)
cam.issuedOnline2017-06-23


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International