title: MEF2C enhances dopaminergic neuron differentiation of human embryonic stem cells in a parkinsonian rat model.
abstract: 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.
authors: Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors: Eun-Gyung
authors: EG
authors: Cho
authors: Jeffrey D
authors: JD
authors: Zaremba
authors: Scott R
authors: SR
authors: McKercher
authors: Maria
authors: M
authors: Talantova
authors: Shichun
authors: S
authors: Tu
authors: Eliezer
authors: E
authors: Masliah
authors: Shing Fai
authors: SF
authors: Chan
authors: Nobuki
authors: N
authors: Nakanishi
authors: Alexey
authors: A
authors: Terskikh
authors: Stuart A
authors: SA
authors: Lipton
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000166:cytology / Q000378:metabolism; D004594:Electrophysiology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000637:transplantation; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D026161:MADS Domain Proteins / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000628:therapy; D016133:Polymerase Chain Reaction; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D018006:Myogenic Regulatory Factors; D016627:Oxidopamine