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REST suppression me...
REST suppression mediates neural conversion of adult human fibroblasts via microRNA-dependent and -independent pathways
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- Drouin-Ouellet, Janelle (author)
- Lund University,Lunds universitet,Utvecklings- och regenerativ neurobiologi,Forskargrupper vid Lunds universitet,Developmental and Regenerative Neurobiology,Lund University Research Groups
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- Lau, Shong (author)
- Lund University,Lunds universitet,Utvecklings- och regenerativ neurobiologi,Forskargrupper vid Lunds universitet,Developmental and Regenerative Neurobiology,Lund University Research Groups
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- Brattås, Per Ludvik (author)
- Lund University,Lunds universitet,Molekylär neurogenetik,Forskargrupper vid Lunds universitet,Molecular Neurogenetics,Lund University Research Groups
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- Ottosson, Daniella (author)
- Lund University,Lunds universitet,Utvecklings- och regenerativ neurobiologi,Forskargrupper vid Lunds universitet,Developmental and Regenerative Neurobiology,Lund University Research Groups
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- Pircs, Karolina (author)
- Lund University,Lunds universitet,Molekylär neurogenetik,Forskargrupper vid Lunds universitet,Molecular Neurogenetics,Lund University Research Groups
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- Grassi, Daniela A (author)
- Lund University,Lunds universitet,Molekylär neurogenetik,Forskargrupper vid Lunds universitet,Molecular Neurogenetics,Lund University Research Groups
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- Collins, Lucy M (author)
- University of Cambridge
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- Vuono, Romina (author)
- University of Cambridge
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- Andersson Sjöland, Annika (author)
- Lund University,Lunds universitet,Lungbiologi,Forskargrupper vid Lunds universitet,Lung Biology,Lund University Research Groups
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- Westergren-Thorsson, Gunilla (author)
- Lund University,Lunds universitet,Lungbiologi,Forskargrupper vid Lunds universitet,Lung Biology,Lund University Research Groups
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- Graff, Caroline (author)
- Karolinska Institutet,Karolinska Institute
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- Minthon, Lennart (author)
- Lund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,Clinical Memory Research,Lund University Research Groups
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- Toresson, Håkan (author)
- Lund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,Clinical Memory Research,Lund University Research Groups
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- Barker, Roger A (author)
- Lund University,Lunds universitet,Utvecklings- och regenerativ neurobiologi,Forskargrupper vid Lunds universitet,Developmental and Regenerative Neurobiology,Lund University Research Groups,University of Cambridge
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- Jakobsson, Johan (author)
- Lund University,Lunds universitet,Molekylär neurogenetik,Forskargrupper vid Lunds universitet,Molecular Neurogenetics,Lund University Research Groups
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- Parmar, Malin (author)
- Lund University,Lunds universitet,Utvecklings- och regenerativ neurobiologi,Forskargrupper vid Lunds universitet,Developmental and Regenerative Neurobiology,Lund University Research Groups
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(creator_code:org_t)
- 2017-06-23
- 2017
- English.
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In: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 9:8, s. 1117-1131
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
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- art (subject category)
- ref (subject category)
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- By the author/editor
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Drouin-Ouellet, ...
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Lau, Shong
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Brattås, Per Lud ...
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Ottosson, Daniel ...
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Pircs, Karolina
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Grassi, Daniela ...
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show more...
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Collins, Lucy M
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Vuono, Romina
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Andersson Sjölan ...
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Westergren-Thors ...
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Graff, Caroline
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Minthon, Lennart
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Toresson, Håkan
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Barker, Roger A
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Jakobsson, Johan
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Parmar, Malin
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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EMBO Molecular M ...
- By the university
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Lund University
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Karolinska Institutet