Reprogramming Human Adult Fibroblasts into GABAergic Interneurons.
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Authors
Kidnapillai, Srisaiyini
Drouin-Ouellet, Janelle
Publication Date
2021-12-08Journal Title
Cells
ISSN
2073-4409
Publisher
MDPI AG
Volume
10
Issue
12
Language
eng
Type
Article
This Version
VoR
Metadata
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Bruzelius, A., Kidnapillai, S., Drouin-Ouellet, J., Stoker, T., Barker, R. A., & Rylander Ottosson, D. (2021). Reprogramming Human Adult Fibroblasts into GABAergic Interneurons.. Cells, 10 (12) https://doi.org/10.3390/cells10123450
Abstract
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.
Keywords
Electrophysiology, Calbindin, Direct Reprogramming, In, Neuronal Conversion, Disease-modelling, Adult Skin Cells, Neuroglia, Interneurons, Fibroblasts, Skin, Humans, Brain Diseases, gamma-Aminobutyric Acid, Repressor Proteins, Cell Differentiation, Gene Expression Regulation, Adult, Neurogenesis, GABAergic Neurons, Cellular Reprogramming, Cognitive Dysfunction
Sponsorship
Wellcome Trust (203151/Z/16/Z)
Medical Research Council (MC_PC_17230)
Identifiers
34943958, PMC8699824
External DOI: https://doi.org/10.3390/cells10123450
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333320
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