Tissue Engineering and Regenerative Medicine 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 neuroprotectivemechanisms ofMIAMI cells and human neural stem cells (NSCs), both adhering to NT3-releasing PAMs in an ex vivo organotypic model of nigrostriatal degeneration made frombrain sagittal slices. Itwas shownthatPAMs led toamarked increase inMIAMI 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 differentiatedmostly intodopaminergic neuronal cellswhenadhering to PAM-NT3.Moreover, those cellswere 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, whichmight 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. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:670–684