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Reprogramming Human Adult Fibroblasts into GABAergic Interneurons
Direct reprogramming is an appealing strategy to generate neurons from a somatic cell by forced expression of transcription factors. The generated neurons can be used for both cell replacement strategies and disease modelling. Using this technique, previous studies have shown that γ-aminobutyric aci...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699824/ https://www.ncbi.nlm.nih.gov/pubmed/34943958 http://dx.doi.org/10.3390/cells10123450 |
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author | Bruzelius, Andreas Kidnapillai, Srisaiyini Drouin-Ouellet, Janelle Stoker, Tom Barker, Roger A. Rylander Ottosson, Daniella |
author_facet | Bruzelius, Andreas Kidnapillai, Srisaiyini Drouin-Ouellet, Janelle Stoker, Tom Barker, Roger A. Rylander Ottosson, Daniella |
author_sort | Bruzelius, Andreas |
collection | PubMed |
description | Direct reprogramming is an appealing strategy to generate neurons from a somatic cell by forced expression of transcription factors. The generated neurons can be used for both cell replacement strategies and disease modelling. Using this technique, previous studies have shown that γ-aminobutyric acid (GABA) expressing interneurons can be generated from different cell sources, such as glia cells or fetal fibroblasts. Nevertheless, the generation of neurons from adult human fibroblasts, an easily accessible cell source to obtain patient-derived neurons, has proved to be challenging due to the intrinsic blockade of neuronal commitment. In this paper, we used an optimized protocol for adult skin fibroblast reprogramming based on RE1 Silencing Transcription Factor (REST) inhibition together with a combination of GABAergic fate determinants to convert human adult skin fibroblasts into GABAergic neurons. Our results show a successful conversion in 25 days with upregulation of neuronal gene and protein expression levels. Moreover, we identified specific gene combinations that converted fibroblasts into neurons of a GABAergic interneuronal fate. Despite the well-known difficulty in converting adult fibroblasts into functional neurons in vitro, we could detect functional maturation in the induced neurons. GABAergic interneurons have relevance for cognitive impairments and brain disorders, such as Alzheimer’s and Parkinson’s diseases, epilepsy, schizophrenia and autism spectrum disorders. |
format | Online Article Text |
id | pubmed-8699824 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-86998242021-12-24 Reprogramming Human Adult Fibroblasts into GABAergic Interneurons Bruzelius, Andreas Kidnapillai, Srisaiyini Drouin-Ouellet, Janelle Stoker, Tom Barker, Roger A. Rylander Ottosson, Daniella Cells Article Direct reprogramming is an appealing strategy to generate neurons from a somatic cell by forced expression of transcription factors. The generated neurons can be used for both cell replacement strategies and disease modelling. Using this technique, previous studies have shown that γ-aminobutyric acid (GABA) expressing interneurons can be generated from different cell sources, such as glia cells or fetal fibroblasts. Nevertheless, the generation of neurons from adult human fibroblasts, an easily accessible cell source to obtain patient-derived neurons, has proved to be challenging due to the intrinsic blockade of neuronal commitment. In this paper, we used an optimized protocol for adult skin fibroblast reprogramming based on RE1 Silencing Transcription Factor (REST) inhibition together with a combination of GABAergic fate determinants to convert human adult skin fibroblasts into GABAergic neurons. Our results show a successful conversion in 25 days with upregulation of neuronal gene and protein expression levels. Moreover, we identified specific gene combinations that converted fibroblasts into neurons of a GABAergic interneuronal fate. Despite the well-known difficulty in converting adult fibroblasts into functional neurons in vitro, we could detect functional maturation in the induced neurons. GABAergic interneurons have relevance for cognitive impairments and brain disorders, such as Alzheimer’s and Parkinson’s diseases, epilepsy, schizophrenia and autism spectrum disorders. MDPI 2021-12-08 /pmc/articles/PMC8699824/ /pubmed/34943958 http://dx.doi.org/10.3390/cells10123450 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Bruzelius, Andreas Kidnapillai, Srisaiyini Drouin-Ouellet, Janelle Stoker, Tom Barker, Roger A. Rylander Ottosson, Daniella Reprogramming Human Adult Fibroblasts into GABAergic Interneurons |
title | Reprogramming Human Adult Fibroblasts into GABAergic Interneurons |
title_full | Reprogramming Human Adult Fibroblasts into GABAergic Interneurons |
title_fullStr | Reprogramming Human Adult Fibroblasts into GABAergic Interneurons |
title_full_unstemmed | Reprogramming Human Adult Fibroblasts into GABAergic Interneurons |
title_short | Reprogramming Human Adult Fibroblasts into GABAergic Interneurons |
title_sort | reprogramming human adult fibroblasts into gabaergic interneurons |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699824/ https://www.ncbi.nlm.nih.gov/pubmed/34943958 http://dx.doi.org/10.3390/cells10123450 |
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