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

Drouin‐Ouellet, Janelle, Lau, Shong, Brattås, Per Ludvik, Rylander Ottosson, Daniella, Pircs, Karolina, Grassi, Daniela A, Collins, Lucy M, Vuono, Romina, Andersson Sjöland, Annika, Westergren‐Thorsson, Gunilla, and others. (2017) REST suppression mediates neural conversion of adult human fibroblasts via microRNA‐dependent and ‐independent pathways. EMBO Molecular Medicine, 9 (8). pp. 1117-1131. ISSN 1757-4676. (doi:10.15252/emmm.201607471) (KAR id:78971)

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. 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.

Item Type: Article
DOI/Identification number: 10.15252/emmm.201607471
Uncontrolled keywords: Medway school of pharmacy
Divisions: Divisions > Division of Natural Sciences > Medway School of Pharmacy
Depositing User: Romina Vuono
Date Deposited: 25 Nov 2019 15:35 UTC
Last Modified: 16 Feb 2021 14:10 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/78971 (The current URI for this page, for reference purposes)

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