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.
| Original language | English |
|---|---|
| Pages (from-to) | 289-304 |
| Number of pages | 16 |
| Journal | Apoptosis |
| Volume | 17 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 2012 |
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Keywords
- Cell therapy
- Cytokines
- Dopamine transporter
- Neural stem cells
- Neurorescue
ASJC Scopus subject areas
- Cell Biology
- Clinical Biochemistry
- Biochemistry, medical
- Cancer Research
- Pharmaceutical Science
- Pharmacology
- Medicine(all)
Cite this
Neuroprotective effects of human mesenchymal stem cells on neural cultures exposed to 6-hydroxydopamine : Implications for reparative therapy in Parkinson's disease. / Cova, Lidia; Bossolasco, Patrizia; Armentero, Marie Therese; Diana, Valentina; Zennaro, Eleonora; Mellone, Manuela; Calzarossa, Cinzia; Cerri, Silvia; Lambertenghi Deliliers, Giorgio; Polli, Elio; Blandini, Fabio; Silani, Vincenzo.
In: Apoptosis, Vol. 17, No. 3, 03.2012, p. 289-304.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Neuroprotective effects of human mesenchymal stem cells on neural cultures exposed to 6-hydroxydopamine
T2 - Implications for reparative therapy in Parkinson's disease
AU - Cova, Lidia
AU - Bossolasco, Patrizia
AU - Armentero, Marie Therese
AU - Diana, Valentina
AU - Zennaro, Eleonora
AU - Mellone, Manuela
AU - Calzarossa, Cinzia
AU - Cerri, Silvia
AU - Lambertenghi Deliliers, Giorgio
AU - Polli, Elio
AU - Blandini, Fabio
AU - Silani, Vincenzo
PY - 2012/3
Y1 - 2012/3
N2 - 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.
AB - 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.
KW - Cell therapy
KW - Cytokines
KW - Dopamine transporter
KW - Neural stem cells
KW - Neurorescue
UR - http://www.scopus.com/inward/record.url?scp=84862272787&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862272787&partnerID=8YFLogxK
U2 - 10.1007/s10495-011-0679-9
DO - 10.1007/s10495-011-0679-9
M3 - Article
C2 - 22160861
AN - SCOPUS:84862272787
VL - 17
SP - 289
EP - 304
JO - Apoptosis : an international journal on programmed cell death
JF - Apoptosis : an international journal on programmed cell death
SN - 1360-8185
IS - 3
ER -