Induction of A9 dopaminergic neurons from neural stem cells improves motor function in an animal model of Parkinson's disease

• Published in: Brain (London, England : 1878) Vol. 131; no. 3; pp. 630 - 641
• Main Authors: O’Keeffe, Fiona E., Scott, Sarah A., Tyers, Pam, O’Keeffe, Gerard W., Dalley, Jeffrey W., Zufferey, Romain, Caldwell, Maeve A.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.03.2008; Oxford Publishing Limited (England)
• Subjects: Animals; Biological and medical sciences; Brain Tissue Transplantation - methods; Cell Differentiation; Cell Survival; Coculture Techniques; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dopamine - biosynthesis; dopamine neurons; Female; Gene Transfer Techniques; Genetic Vectors; Homeodomain Proteins - metabolism; Lentivirus - genetics; Medical sciences; Mesencephalon - transplantation; Motor Activity; neural stem cells; Neurology; Neurons - pathology; Neurons - transplantation; Parkinson Disease - metabolism; Parkinson Disease - physiopathology; Parkinson Disease - therapy; Parkinson's disease; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction - methods; Stem Cell Transplantation - methods; Tissue Culture Techniques; transcription factors; Transcription Factors - metabolism; dopamine neurons; Parkinson's disease; neural stem cells; transcription factors; Animal model; Nervous system diseases; Dopamine; Stem cell; Parkinson disease; Catecholamine; Cerebral disorder; Central nervous system disease; Neurotransmitter; Dopaminergic neuron; Degenerative disease; Extrapyramidal syndrome
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awm340

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.