期刊
EMBO MOLECULAR MEDICINE
卷 9, 期 8, 页码 1117-1131出版社
WILEY
DOI: 10.15252/emmm.201607471
关键词
adult human dermal fibroblasts; induced neurons; microRNAs 9; 9*and 124; RE1-silencing transcription factor
资金
- New York Stem Cell Foundation
- European Research Council under the European Union's Seventh Framework Programme: FP Neuro Stem Cell Repair [602278]
- ERC [30971]
- Swedish Research Council [521-2012-5624, 2016-00873, 70862601/Bagadilico]
- Swedish Parkinson Foundation (Parkinsonfonden)
- Strategic Research Area at Lund University Multipark (multidisciplinary research in Parkinson's disease)
- Canadian Institutes of Health Research (CIHR) fellowship [358492]
- Swedish Foundation for Strategic Research [FFL12-0074]
- NIHR Biomedical Research Centre
- Swedish Foundation for Strategic Research (SSF) [FFL12-0074] Funding Source: Swedish Foundation for Strategic Research (SSF)
- Medical Research Council [MC_PC_12009] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0616-10011] Funding Source: researchfish
Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons (iNs), was achieved for the first time 6years 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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