title: Reducing glypican-4 in ES cells improves recovery in a rat model of Parkinson's disease by increasing the production of dopaminergic neurons and decreasing teratoma formation.
abstract: The heparan sulfate proteoglycan Glypican 4 (Gpc4) is strongly expressed in mouse embryonic stem (ES) cells where it controls the maintenance of self-renewal by modulating Wnt/β-catenin signaling activities. Here we show that mouse ES cells carrying a hypomorphic Gpc4 allele, in a single-step neuronal differentiation protocol, show increased differentiation into dopaminergic neurons expressing tyrosine hydroxylase (TH) and nuclear receptor related-1 protein (Nurr1) 1. In contrast to wild-type cells, these differentiating Gpc4-mutant cells expressed high levels of DOPA decarboxylase and the dopamine transporter, two markers expressed by fully mature dopaminergic neurons. Intrastriatal transplantation of Gpc4 hypomorphic cells into a 6-OHDA rat model for Parkinson's disease improved motor behavior in the cylinder test and amphetamine-induced rotations at a higher level than transplanted wild-type cells. Importantly, Gpc4 hypomorphic cell grafts, in contrast to wild-type cells, did not generate teratomas in the host brains, leading to strongly enhanced animal survival. Therefore, control of Gpc4 activity level represents a new potential strategy to reduce ES cell tumorigenic features while at the same time increasing neuronal differentiation and integration.
authors.affiliation: Aix-Marseille University, Centre National de la Recherche Scientifique, Marseille, IBDM, UMR7288, Marseille, France.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Fico
authors.affiliation: Aix-Marseille University, Centre National de la Recherche Scientifique, Marseille, IBDM, UMR7288, Marseille, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: de Chevigny
authors.affiliation: Aix-Marseille University, Centre National de la Recherche Scientifique, Marseille, IBDM, UMR7288, Marseille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Melon
authors.affiliation: Aix-Marseille University, Centre National de la Recherche Scientifique, Marseille, IBDM, UMR7288, Marseille, France.
authors.forename: Manon
authors.initials: M
authors.lastname: Bohic
authors.affiliation: Aix-Marseille University, Centre National de la Recherche Scientifique, Marseille, IBDM, UMR7288, Marseille, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Kerkerian-Le Goff
authors.affiliation: Aix-Marseille University, Centre National de la Recherche Scientifique, Marseille, IBDM, UMR7288, Marseille, France.
authors.forename: Flavio
authors.initials: F
authors.lastname: Maina
authors.affiliation: Aix-Marseille University, Centre National de la Recherche Scientifique, Marseille, IBDM, UMR7288, Marseille, France rosanna.dono@univ-amu.fr harold.cremer@univ-amu.fr.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Dono
authors.affiliation: Aix-Marseille University, Centre National de la Recherche Scientifique, Marseille, IBDM, UMR7288, Marseille, France rosanna.dono@univ-amu.fr harold.cremer@univ-amu.fr.
authors.forename: Harold
authors.initials: H
authors.lastname: Cremer
mesh_terms: D000818:Animals; D064026:Calbindins / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000637:transplantation*; D053673:Glypicans / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D006801:Humans; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D010300:Parkinson Disease / Q000503:physiopathology* / Q000601:surgery*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology; D013724:Teratoma / Q000209:etiology / Q000517:prevention & control*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D064026:Calbindins; D050483:Dopamine Plasma Membrane Transport Proteins; C496504:Foxa2 protein, rat; D053673:Glypicans; D017448:Receptors, Dopamine D2; C113776:dopamine D2L receptor; D051542:Hepatocyte Nuclear Factor 3-beta; D049452:Green Fluorescent Proteins; D014446:Tyrosine 3-Monooxygenase