title: Induction of A9 dopaminergic neurons from neural stem cells improves motor function in an animal model of Parkinson's disease.
abstract: Neural stem cells (NSCs) are widely endorsed as a cell source for replacement strategies in neurodegenerative disease. However, their usefulness is currently limited by the inability to induce specific neurotransmitter phenotypes in these cells. In order to direct dopaminergic neuronal fate, we overexpressed Pitx3 in NSCs that were then exposed to E11 developing ventral mesencephalon (VM) in explant culture. This resulted in a significant potentiation of dopaminergic differentiation of the cells. When transplanted into the 6-hydroxydopamine lesioned Parkinsonian rats, these cografts of VM and Pitx3 overexpressing NSCs resulted in a significant restitution of motor function. In addition, there were greater numbers of Girk2 positive A9 neurons in the periphery of the transplants that were NSC derived. This demonstrates that given the correct signals, NSCs can be induced to become dopaminergic neurons that can differentiate into the correct nigrastriatal phenotype required for the treatment of Parkinson's disease.
authors.affiliation: Cambridge Center for Brain Repair and Department of Clinical Neurosciences, Forvie Site, Robinsons Way, Cambridge CB2 2PY, UK.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: O'Keeffe
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Scott
authors.forename: Pam
authors.initials: P
authors.lastname: Tyers
authors.forename: Gerard W
authors.initials: GW
authors.lastname: O'Keeffe
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Dalley
authors.forename: Romain
authors.initials: R
authors.lastname: Zufferey
authors.forename: Maeve A
authors.initials: MA
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D016380:Brain Tissue Transplantation / Q000379:methods*; D002454:Cell Differentiation; D002470:Cell Survival; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004298:Dopamine / Q000096:biosynthesis*; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008636:Mesencephalon / Q000637:transplantation; D009043:Motor Activity; D009474:Neurons / Q000473:pathology / Q000637:transplantation; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D033581:Stem Cell Transplantation / Q000379:methods*; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; C433629:homeobox protein PITX3; D004298:Dopamine