title: Transplantation of neuronal-primed human bone marrow mesenchymal stem cells in hemiparkinsonian rodents.
abstract: Bone marrow-derived human mesenchymal stem cells (hMSCs) have shown promise in in vitro neuronal differentiation and in cellular therapy for neurodegenerative disorders, including Parkinson' disease. However, the effects of intracerebral transplantation are not well defined, and studies do not agreed on the optimal neuronal differentiation method. Here, we investigated three growth factor-based neuronal differentiation procedures (using FGF-2/EGF/PDGF/SHH/FGF-8/GDNF), and found all to be capable of eliciting an immature neural phenotype, in terms of cell morphology and gene/protein expression. The neuronal-priming (FGF-2/EGF) method induced neurosphere-like formation and the highest NES and NR4A2 expression by hMSCs. Transplantation of undifferentiated and neuronal-primed hMSCs into the striatum and substantia nigra of 6-OHDA-lesioned hemiparkinsonian rats revealed transient graft survival of 7 days, despite the reported immunosuppressive properties of MSCs and cyclosporine-immunosuppression of rats. Neither differentiation of hMSCs nor induction of host neurogenesis was observed at injection sites, and hMSCs continued producing mesodermal fibronectin. Strategies for improving engraftment and differentiation post-transplantation, such as prior in vitro neuronal-priming, nigral and striatal grafting, and co-transplantation of olfactory ensheathing cells that promote neural regeneration, were unable to provide advantages. Innate inflammatory responses (Iba-1-positive microglia/macrophage and GFAP-positive astrocyte activation and accumulation) were detected around grafts within 7 days. Our findings indicate that growth factor-based methods allow hMSC differentiation toward immature neuronal-like cells, and contrary to previous reports, only transient survival and engraftment of hMSCs occurs following transplantation in immunosuppressed hemiparkinsonian rats. In addition, suppression of host innate inflammatory responses may be a key factor for improving hMSC survival and engraftment.
authors.affiliation: Blood Stem Cells and Cancer Research, St Vincent's Centre for Applied Medical Research, Sydney, New South Wales, Australia.
authors.forename: Melissa L M
authors.initials: ML
authors.lastname: Khoo
authors.forename: Helen
authors.initials: H
authors.lastname: Tao
authors.forename: Adrian C B
authors.initials: AC
authors.lastname: Meedeniya
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay-Sim
authors.forename: David D F
authors.initials: DD
authors.lastname: Ma
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000254:growth & development / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010300:Parkinson Disease / Q000628:therapy*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C496456:FGF8 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D053823:Hedgehog Proteins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; C509239:SHH protein, human; C075278:platelet-derived growth factor A; D016222:Fibroblast Growth Factor 2; D051524:Fibroblast Growth Factor 8; D004815:Epidermal Growth Factor