Resumen de Effects of a neuroprotective stem cell therapy involving Mesenchymal Stem Cells (MSCs) secreting the Glial cell line-Derived Neurotrophic Factor (GDNF) in Parkinsonian mice from short to long-term
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease (AD). The major symptoms of the disease are rigidity, tremor and bradykinesia. These motor symptoms result from the degeneration of the nigrostriatal dopaminergic neurons (DAn). For 90-95 % of the patients, the etiology of the disease remains unknown and until now, no cure exists. In fact, the current medications offered to the patients are only able to alleviate the symptoms for limited time and causing strong side effects.
Therefore, investigating new therapeutic strategies is essential. The aim of the thesis was to investigate a neuroprotective strategy for PD, combining gene and cellular therapies. This strategy involves the generation and transplantation into the striatum (Str) of a parkinsonian MPTP mouse model, of adipose-derived human mesenchymal stem cells (MSCs) releasing the glial cell line-derived neurotrophic factor (GDNF). MSCs are multipotent stem cells present in different tissues in the adult, such as adipose tissue and bone marrow. The hypothesis was that the transplanted GDNF-mCherry-MSCs could protect the degenerating DAn from further loss by providing a protective environment via the secretion of GDNF and/or other factors.
This protection would rescue the nigrostriatal pathway and hence the neurological and motor deficits of the parkinsonian mice. Two genetically modified MSCs lines were generated via lentiviral transductions and Fluorescence Activated Cell Sorting (FACS): GDNF-mCherry-MSCs line that secretes GDNF, and the control line mCherry-MSCs. Differentiation towards adipocytes and osteocytes revealed that the genetically modified cells kept their multipotency capacities. Some transplanted GDNF-mCherry-MSCs and mCherry-MSCs were found in the Str until four months post-transplant, however the survival rates were low.
Furthermore, some immune reactions against the grafts were found, mostly involving macrophages. Both transplant types induced a partial recovery of the DAn from the nigrostriatal pathway, especially in the regions close to the transplantation sites. The open field test (OFT) highlighted some locomotor deficits of the parkinsonian mice. However, the recovery of the nigrostriatal pathway was not sufficient to rescue these deficits. Therefore, this thesis showed the generation of a MSC line secreting GDNF as a therapeutic tool for neurodegenerative diseases. Moreover, it showed the partial neuroprotective efficiency of both GDNF-mCherry-MSCs and mCherry-MSCs on the recovery of the nigrostriatal DAn and their effects on the parkinsonian mice’ behaviour. This work is a proof of concept for the creation of customized stem cell therapies involving MSCs that can be used from autologous sources.
