REST suppression mediates neural conversion of adult human fibroblasts via microRNA‐dependent and ‐independent pathways
Autor: | Per Ludvik Brattås, Daniella Rylander Ottosson, Romina Vuono, Lucy M Collins, Lennart Minthon, Janelle Drouin-Ouellet, Johan Jakobsson, Annika Andersson Sjöland, Daniela A. Grassi, Caroline Graff, Shong Lau, Malin Parmar, Håkan Toresson, Roger A. Barker, Karolina Pircs, Gunilla Westergren-Thorsson |
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Přispěvatelé: | Jakobsson, Johan [0000-0003-0669-7673], Parmar, Malin [0000-0001-5002-4199], Apollo - University of Cambridge Repository |
Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Adult Cytological Techniques Repressor RE1-silencing transcription factor Biology Bioinformatics Chromatin Epigenetics Genomics & Functional Genomics 03 medical and health sciences microRNA Gene Knockdown Techniques adult human dermal fibroblasts Humans microRNAs 9/9* and 124 Gene Research Articles RE1‐silencing transcription factor Neurons Gene knockdown Stem Cells Gene Expression Profiling Fibroblasts Cell biology Gene expression profiling induced neurons Repressor Proteins MicroRNAs 030104 developmental biology Cell Transdifferentiation biology.protein Molecular Medicine Reprogramming Research Article Neuroscience |
Zdroj: | BASE-Bielefeld Academic Search Engine EMBO Molecular Medicine |
ISSN: | 1757-4676 |
Popis: | 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 Parkinson9s, Huntington9s, as well as Alzheimer9s disease. |
Databáze: | OpenAIRE |
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