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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...

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Autores principales: Bruzelius, Andreas, Kidnapillai, Srisaiyini, Drouin-Ouellet, Janelle, Stoker, Tom, Barker, Roger A., Rylander Ottosson, Daniella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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