Survival, differentiation, and neuroprotective mechanisms of human stem cells complexed with neurotrophin-3-releasing pharmacologically active microcarriers in an ex vivo model of Parkinson's disease.
Stem cell-based regenerative therapies hold great potential for the treatment of degenerative disorders such as Parkinson's disease (PD). We recently reported the repair and functional recovery after treatment with human marrow-isolated adult multilineage inducible (MIAMI) cells adhered to neurotrophin-3 (NT3) releasing pharmacologically active microcarriers (PAMs) in hemiparkinsonian rats. In order to comprehend this effect, the goal of the present work was to elucidate the survival, differentiation, and neuroprotective mechanisms of MIAMI cells and human neural stem cells (NSCs), both adhering to NT3-releasing PAMs in an ex vivo organotypic model of nigrostriatal degeneration made from brain sagittal slices. It was shown that PAMs led to a marked increase in MIAMI cell survival and neuronal differentiation when releasing NT3. A significant neuroprotective effect of MIAMI cells adhering to PAMs was also demonstrated. NSCs barely had a neuroprotective effect and differentiated mostly into dopaminergic neuronal cells when adhering to PAM-NT3. Moreover, those cells were able to release dopamine in a sufficient amount to induce a return to baseline levels. Reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay analyses identified vascular endothelial growth factor (VEGF) and stanniocalcin-1 as potential mediators of the neuroprotective effect of MIAMI cells and NSCs, respectively. It was also shown that VEGF locally stimulated tissue vascularization, which might improve graft survival, without excluding a direct neuroprotective effect of VEGF on dopaminergic neurons. These results indicate a prospective interest of human NSC/PAM and MIAMI cell/PAM complexes in tissue engineering for PD.


CONCLUSIONS
Stem cell-based regenerative therapies hold great potential for the treatment of degenerative disorders such as Parkinson's disease (PD). The present work elucidates and compares the survival, differentiation, and neuroprotective mechanisms of marrow-isolated adult multilineage inducible cells and human neural stem cells both adhered to neurotrophin-3-releasing pharmacologically active microcarriers in an ex vivo organotypic model of PD made from brain sagittal slices.
INSERM U1066, Micro et nanomédecines biomimétiques, Angers, France; L'université Nantes, Angers, Le Mans, Angers University, Angers, France; Pharmacy and Pharmaceutical Technology Department, University of Navarra, Pamplona, Spain; Department of Molecular Biology and Center of Molecular Biology "Severo Ochoa," Autonomous University of Madrid-Consejo Superior de Investigaciones Científicas, Campus Cantoblanco, Madrid, Spain; Miami Veterans Healthcare System, Department of Orthopedics, and Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Nicolas
N
Daviaud
INSERM U1066, Micro et nanomédecines biomimétiques, Angers, France; L'université Nantes, Angers, Le Mans, Angers University, Angers, France; Pharmacy and Pharmaceutical Technology Department, University of Navarra, Pamplona, Spain; Department of Molecular Biology and Center of Molecular Biology "Severo Ochoa," Autonomous University of Madrid-Consejo Superior de Investigaciones Científicas, Campus Cantoblanco, Madrid, Spain; Miami Veterans Healthcare System, Department of Orthopedics, and Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Elisa
E
Garbayo
INSERM U1066, Micro et nanomédecines biomimétiques, Angers, France; L'université Nantes, Angers, Le Mans, Angers University, Angers, France; Pharmacy and Pharmaceutical Technology Department, University of Navarra, Pamplona, Spain; Department of Molecular Biology and Center of Molecular Biology "Severo Ochoa," Autonomous University of Madrid-Consejo Superior de Investigaciones Científicas, Campus Cantoblanco, Madrid, Spain; Miami Veterans Healthcare System, Department of Orthopedics, and Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Laurence
L
Sindji
INSERM U1066, Micro et nanomédecines biomimétiques, Angers, France; L'université Nantes, Angers, Le Mans, Angers University, Angers, France; Pharmacy and Pharmaceutical Technology Department, University of Navarra, Pamplona, Spain; Department of Molecular Biology and Center of Molecular Biology "Severo Ochoa," Autonomous University of Madrid-Consejo Superior de Investigaciones Científicas, Campus Cantoblanco, Madrid, Spain; Miami Veterans Healthcare System, Department of Orthopedics, and Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Alberto
A
Martínez-Serrano
INSERM U1066, Micro et nanomédecines biomimétiques, Angers, France; L'université Nantes, Angers, Le Mans, Angers University, Angers, France; Pharmacy and Pharmaceutical Technology Department, University of Navarra, Pamplona, Spain; Department of Molecular Biology and Center of Molecular Biology "Severo Ochoa," Autonomous University of Madrid-Consejo Superior de Investigaciones Científicas, Campus Cantoblanco, Madrid, Spain; Miami Veterans Healthcare System, Department of Orthopedics, and Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Paul C
PC
Schiller
INSERM U1066, Micro et nanomédecines biomimétiques, Angers, France; L'université Nantes, Angers, Le Mans, Angers University, Angers, France; Pharmacy and Pharmaceutical Technology Department, University of Navarra, Pamplona, Spain; Department of Molecular Biology and Center of Molecular Biology "Severo Ochoa," Autonomous University of Madrid-Consejo Superior de Investigaciones Científicas, Campus Cantoblanco, Madrid, Spain; Miami Veterans Healthcare System, Department of Orthopedics, and Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, USA claudia.montero-menei@univ-angers.fr.
Claudia N
CN
Montero-Menei
D000328:Adult; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D018914:Cells, Immobilized / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D003692:Delayed-Action Preparations / Q000494:pharmacology; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000494:pharmacology*; D006801:Humans; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D020933:Neurotrophin 3 / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051381:Rats; D033581:Stem Cell Transplantation
D003692:Delayed-Action Preparations; D004337:Drug Carriers; D020933:Neurotrophin 3
Laminin; Mesenchymal stem cells; Neural stem cells; Neurotrophin-3; Organotypic slice culture; Stanniocalcin-1; Tissue engineering; Vascular endothelial growth factor