title: Neuroprotective effects of human mesenchymal stem cells on neural cultures exposed to 6-hydroxydopamine: implications for reparative therapy in Parkinson's disease.
abstract: Stem cell (SC) transplantation represents a promising tool to treat neurodegenerative disorders, such as Parkinson's disease (PD), but positive therapeutic outcomes require elucidation of the biological mechanisms involved. Therefore, we investigated human Mesenchymal SCs (hMSCs) ability to protect murine differentiated Neural SCs (mdNSCs) against the cytotoxic effects of 6-hydroxydopamine (6-OHDA) in a co-culture model mimicking the in vivo neurovascular niche. The internalization of 6-OHDA mainly relies on its uptake by the dopamine active transporter (DAT), but its toxicity could also involve other pathways. We demonstrated that mdNSCs consistently expressed DAT along the differentiative process. Exposure to 6-OHDA did not affect hMSCs, but induced DAT-independent apoptosis in mdNSCs with generation of reactive oxygen species and caspases 3/7 activation. The potential neuroprotective action of hMSCs on mdNSCs exposed to 6-OHDA was tested in different co-culture conditions, in which hMSCs were added to mdNSCs prior to, simultaneously, or after 6-OHDA treatment. In the presence of the neurotoxin, the majority of mdNSCs acquired an apoptotic phenotype, while co-cultures with hMSCs significantly increased their survival (up to 70%) in all conditions. Multiplex human angiogenic array analysis on the conditioned media demonstrated that cytokine release by hMSCs was finely modulated. Moreover, sole growth factor addition yielded a similar neuroprotective effect on mdNSCs. In conclusion, our findings demonstrate that hMSCs protect mdNSCs against 6-OHDA neurotoxicity, and rescue cells from ongoing neurodegeneration likely through the release of multiple cytokines. Our findings provide novel insights for the development of therapeutic strategies designed to counteract the neurodegenerative processes of PD.
authors.affiliation: Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano 20149, Milan, Italy. l.cova@auxologico.it
authors.forename: Lidia
authors.initials: L
authors.lastname: Cova
authors.forename: Patrizia
authors.initials: P
authors.lastname: Bossolasco
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Armentero
authors.forename: Valentina
authors.initials: V
authors.lastname: Diana
authors.forename: Eleonora
authors.initials: E
authors.lastname: Zennaro
authors.forename: Manuela
authors.initials: M
authors.lastname: Mellone
authors.forename: Cinzia
authors.initials: C
authors.lastname: Calzarossa
authors.forename: Silvia
authors.initials: S
authors.lastname: Cerri
authors.forename: Giorgio Lambertenghi
authors.initials: GL
authors.lastname: Deliliers
authors.forename: Elio
authors.initials: E
authors.lastname: Polli
authors.forename: Fabio
authors.initials: F
authors.lastname: Blandini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Silani
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000628:therapy; D051381:Rats
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D016627:Oxidopamine