دورية أكاديمية
REST suppression mediates neural conversion of adult human fibroblasts via microRNA‐dependent and ‐independent pathways
| العنوان: | REST suppression mediates neural conversion of adult human fibroblasts via microRNA‐dependent and ‐independent pathways |
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| المؤلفون: | Janelle Drouin‐Ouellet, Shong Lau, Per Ludvik Brattås, Daniella Rylander Ottosson, Karolina Pircs, Daniela A Grassi, Lucy M Collins, Romina Vuono, Annika Andersson Sjöland, Gunilla Westergren‐Thorsson, Caroline Graff, Lennart Minthon, Håkan Toresson, Roger A Barker, Johan Jakobsson, Malin Parmar |
| المصدر: | EMBO Molecular Medicine, Vol 9, Iss 8, Pp 1117-1131 (2017) |
| بيانات النشر: | Springer Nature, 2017. |
| سنة النشر: | 2017 |
| المجموعة: | LCC:Medicine (General) LCC:Genetics |
| مصطلحات موضوعية: | adult human dermal fibroblasts, induced neurons, microRNAs 9/9* and 124, RE1‐silencing transcription factor, Medicine (General), R5-920, Genetics, QH426-470 |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1757-4684 1757-4676 20160747 |
| العلاقة: | https://doaj.org/toc/1757-4676Test; https://doaj.org/toc/1757-4684Test |
| DOI: | 10.15252/emmm.201607471 |
| الوصول الحر: | https://doaj.org/article/e73f830423c14f13b05bd7371e571788Test |
| رقم الانضمام: | edsdoj.73f830423c14f13b05bd7371e571788 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 17574684 17574676 20160747 |
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| DOI: | 10.15252/emmm.201607471 |