MEF2C Enhances Dopaminergic Neuron Differentiation of Human Embryonic Stem Cells in a Parkinsonian Rat Model

Human embryonic stem cells (hESCs) can potentially differentiate into any cell type, including dopaminergic neurons to treat Parkinson's disease (PD), but hyperproliferation and tumor formation must be avoided. Accordingly, we use myocyte enhancer factor 2C (MEF2C) as a neurogenic and anti-apop...

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Autores principales: Cho, Eun-Gyung, Zaremba, Jeffrey D., McKercher, Scott R., Talantova, Maria, Tu, Shichun, Masliah, Eliezer, Chan, Shing Fai, Nakanishi, Nobuki, Terskikh, Alexey, Lipton, Stuart A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162026/
https://www.ncbi.nlm.nih.gov/pubmed/21901155
http://dx.doi.org/10.1371/journal.pone.0024027
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author Cho, Eun-Gyung
Zaremba, Jeffrey D.
McKercher, Scott R.
Talantova, Maria
Tu, Shichun
Masliah, Eliezer
Chan, Shing Fai
Nakanishi, Nobuki
Terskikh, Alexey
Lipton, Stuart A.
author_facet Cho, Eun-Gyung
Zaremba, Jeffrey D.
McKercher, Scott R.
Talantova, Maria
Tu, Shichun
Masliah, Eliezer
Chan, Shing Fai
Nakanishi, Nobuki
Terskikh, Alexey
Lipton, Stuart A.
author_sort Cho, Eun-Gyung
collection PubMed
description Human embryonic stem cells (hESCs) can potentially differentiate into any cell type, including dopaminergic neurons to treat Parkinson's disease (PD), but hyperproliferation and tumor formation must be avoided. Accordingly, we use myocyte enhancer factor 2C (MEF2C) as a neurogenic and anti-apoptotic transcription factor to generate neurons from hESC-derived neural stem/progenitor cells (NPCs), thus avoiding hyperproliferation. Here, we report that forced expression of constitutively active MEF2C (MEF2CA) generates significantly greater numbers of neurons with dopaminergic properties in vitro. Conversely, RNAi knockdown of MEF2C in NPCs decreases neuronal differentiation and dendritic length. When we inject MEF2CA-programmed NPCs into 6-hydroxydopamine—lesioned Parkinsonian rats in vivo, the transplanted cells survive well, differentiate into tyrosine hydroxylase-positive neurons, and improve behavioral deficits to a significantly greater degree than non-programmed cells. The enriched generation of dopaminergic neuronal lineages from hESCs by forced expression of MEF2CA in the proper context may prove valuable in cell-based therapy for CNS disorders such as PD.
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spelling pubmed-31620262011-09-07 MEF2C Enhances Dopaminergic Neuron Differentiation of Human Embryonic Stem Cells in a Parkinsonian Rat Model Cho, Eun-Gyung Zaremba, Jeffrey D. McKercher, Scott R. Talantova, Maria Tu, Shichun Masliah, Eliezer Chan, Shing Fai Nakanishi, Nobuki Terskikh, Alexey Lipton, Stuart A. PLoS One Research Article Human embryonic stem cells (hESCs) can potentially differentiate into any cell type, including dopaminergic neurons to treat Parkinson's disease (PD), but hyperproliferation and tumor formation must be avoided. Accordingly, we use myocyte enhancer factor 2C (MEF2C) as a neurogenic and anti-apoptotic transcription factor to generate neurons from hESC-derived neural stem/progenitor cells (NPCs), thus avoiding hyperproliferation. Here, we report that forced expression of constitutively active MEF2C (MEF2CA) generates significantly greater numbers of neurons with dopaminergic properties in vitro. Conversely, RNAi knockdown of MEF2C in NPCs decreases neuronal differentiation and dendritic length. When we inject MEF2CA-programmed NPCs into 6-hydroxydopamine—lesioned Parkinsonian rats in vivo, the transplanted cells survive well, differentiate into tyrosine hydroxylase-positive neurons, and improve behavioral deficits to a significantly greater degree than non-programmed cells. The enriched generation of dopaminergic neuronal lineages from hESCs by forced expression of MEF2CA in the proper context may prove valuable in cell-based therapy for CNS disorders such as PD. Public Library of Science 2011-08-25 /pmc/articles/PMC3162026/ /pubmed/21901155 http://dx.doi.org/10.1371/journal.pone.0024027 Text en Cho et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Cho, Eun-Gyung
Zaremba, Jeffrey D.
McKercher, Scott R.
Talantova, Maria
Tu, Shichun
Masliah, Eliezer
Chan, Shing Fai
Nakanishi, Nobuki
Terskikh, Alexey
Lipton, Stuart A.
MEF2C Enhances Dopaminergic Neuron Differentiation of Human Embryonic Stem Cells in a Parkinsonian Rat Model
title MEF2C Enhances Dopaminergic Neuron Differentiation of Human Embryonic Stem Cells in a Parkinsonian Rat Model
title_full MEF2C Enhances Dopaminergic Neuron Differentiation of Human Embryonic Stem Cells in a Parkinsonian Rat Model
title_fullStr MEF2C Enhances Dopaminergic Neuron Differentiation of Human Embryonic Stem Cells in a Parkinsonian Rat Model
title_full_unstemmed MEF2C Enhances Dopaminergic Neuron Differentiation of Human Embryonic Stem Cells in a Parkinsonian Rat Model
title_short MEF2C Enhances Dopaminergic Neuron Differentiation of Human Embryonic Stem Cells in a Parkinsonian Rat Model
title_sort mef2c enhances dopaminergic neuron differentiation of human embryonic stem cells in a parkinsonian rat model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162026/
https://www.ncbi.nlm.nih.gov/pubmed/21901155
http://dx.doi.org/10.1371/journal.pone.0024027
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