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Pharmacological Transdifferentiation of Human Nasal Olfactory Stem Cells into Dopaminergic Neurons

Authors :
Sophie Landron
Audrey Chabrat
Alain Dupront
Rodolphe Billiras
Francois Feron
Clotilde Mannoury la Cour
Francis Cogé
David Piwnica
Emmanuel Nivet
Esther Schenker
Hélène Darville
Amélie Pontisso-Mahout
Emmanuelle Lacassagne
Institut de Recherches SERVIER (IRS)
Institut de neurophysiopathologie (INP)
Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Centre d'Investigation Clinique [Hôpital de la Conception - APHM] (CIC)
Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Paoli-Calmettes
Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)
This work was supported by the Institut de Recherches Servier (IDRS, Croissy sur Seine). The project is part of the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 116060 (IMPRiND). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations. This work is supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 17.00038.
Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
FERON, Francois
Source :
Stem Cells International, Stem Cells International, 2019, 2019, pp.eCollection 2019. ⟨10.1155/2019/2945435⟩, Stem Cells International, Hindawi Publishing Corporation, 2019, 2019, pp.eCollection 2019. ⟨10.1155/2019/2945435⟩, Stem Cells International, Vol 2019 (2019)

Abstract

The discovery of novel drugs for neurodegenerative diseases has been a real challenge over the last decades. The development of patient- and/or disease-specificin vitromodels represents a powerful strategy for the development and validation of lead candidates in preclinical settings. The implementation of a reliable platform modeling dopaminergic neurons will be an asset in the study of dopamine-associated pathologies such as Parkinson’s disease. Disease models based on cell reprogramming strategies, using either human-induced pluripotent stem cells or transcription factor-mediated transdifferentiation, are among the most investigated strategies. However, multipotent adult stem cells remain of high interest to devise direct conversion protocols and establishin vitromodels that could bypass certain limitations associated with reprogramming strategies. Here, we report the development of a six-step chemically defined protocol that drives the transdifferentiation of human nasal olfactory stem cells into dopaminergic neurons. Morphological changes were progressively accompanied by modifications matching transcript and protein dopaminergic signatures such as LIM homeobox transcription factor 1 alpha (LMX1A), LMX1B, and tyrosine hydroxylase (TH) expression, within 42 days of differentiation. Phenotypic changes were confirmed by the production of dopamine from differentiated neurons. This new strategy paves the way to develop more disease-relevant models by establishing reprogramming-free patient-specific dopaminergic cell models for drug screening and/or target validation for neurodegenerative diseases.

Details

Language :
English
ISSN :
16879678 and 1687966X
Volume :
2019
Database :
OpenAIRE
Journal :
Stem Cells International
Accession number :
edsair.doi.dedup.....9c9f84bd723dfc451a150640099319f3
Full Text :
https://doi.org/10.1155/2019/2945435