Fibroblast growth factor-20 promotes the differentiation of Nurr1-overexpressing neural stem cells into tyrosine hydroxylase-positive neurons.
Stem cells are currently considered as alternative cell resources for restorative transplantation strategies in Parkinson's disease. However, the mechanisms that induce differentiation of a stem cell toward the dopaminergic phenotype are still partly unknown thus hampering the production of dopaminergic neurons from stem cells. In the past, FGF-20 has been found to promote the survival of ventral mesencephalic (VM) dopaminergic (DA) neurons in culture. We hereby provide evidence that FGF-20, a growth factor of the FGF family, is expressed in the adult and 6-OHDA-lesioned striatum and substantia nigra, but is not expressed by VM glia or DA neurons, suggesting that FGF-20 may work on DA neurons in a paracrine- or target-derived manner. We also found that co-culture of Nurr1-NSCs with Schwann cells overexpressing FGF-20 induced the acquisition of a neuronal morphology by the NSCs and the expression of tyrosine hydroxylase (TH) as assessed by immunocytochemistry, cell ELISA, and Western blot analysis. RT-PCR showed, that both, Schwann cells and Nurr1-NSCs (differentiated or not), expressed the FGF-1 receptor suggesting that both direct and indirect actions of FGF-20 are possible. We show that differentiated Nurr1 cells retained both neuronal morphology and TH expression after transplantation into the striatum of 6-OHDA-lesioned postnatal or adult rats, but that neuritogenesis was only observed after postnatal grafts. Thus, our results suggest that FGF-20 promotes the differentiation of Nurr1-NSCs into TH-positive neurons and that additional factors are required for the efficient differentiation of DA neurons in the adult brain.
Grothe
C
C
Hannover Medical School, Department of Neuroanatomy, D-30623 Hannover, Germany. grothe.claudia@mh-hannover.de
Timmer
M
M
Scholz
T
T
Winkler
C
C
Nikkhah
G
G
Claus
P
P
Itoh
N
N
Arenas
E
E
D000818:Animals; D001927:Brain Diseases / Q000139:chemically induced / Q000378:metabolism / Q000601:surgery; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003342:Corpus Striatum / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D008474:Medial Forebrain Bundle / Q000187:drug effects; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism* / Q000637:transplantation; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D016627:Oxidopamine / Q000494:pharmacology; D010641:Phenotype; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D004268:DNA-Binding Proteins; C498812:Fgf20 protein, mouse; C498813:Fgf20 protein, rat; C539883:Nr4a2 protein, mouse; C539884:Nr4a2 protein, rat; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D017468:Receptors, Fibroblast Growth Factor; D014157:Transcription Factors; D005346:Fibroblast Growth Factors; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine