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Cell fusion-mediated reprogramming as neuronal rescue mechanism in Parkinson’s disease

Final Report Summary - REPROGRAMMING FOR PD (Cell fusion-mediated reprogramming as neuronal rescue mechanism in Parkinson’s disease)

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's dementia, and the most common neurodegenerative movement disorder; it affects about 1 % of the population above the age of 60. Clinically, classical PD is characterised by resting tremor, slowness of movement, rigidity, and postural instability. All of these are attributed to a dramatic loss of dopamine (DA)-containing neurons in the substantia nigra pars compacta (SNpc), which leads to DA depletion in the striatum. Over the past century, the growth rate of the population aged 60 and over in industrialised countries has far exceeded that of the population as a whole. Thus, it can be anticipated that over the next generation the proportion of elderly citizens will double, as will the number of individuals suffering from PD, as well as the magnitude of the emotional, physical, and financial burden on patients, caregivers, and society related to this disabling illness. Many attempts have been made to set up an efficient therapy for PD; however, despite all of these efforts to date, therapeutical solutions have not been forthcoming.

Replacement of damaged DA neurons with their fusion with adult stem cells (ASCs) after bone marrow stem cells (BMSCs) transplantation is an attractive possible route to the restoration of neurological functions in PD. Since fusion of BMSCs with somatic cells may account for some of the findings of BMSCs-neuronal differentiation in vivo and, indeed, the Wnt/ß-catenin pathway in embryonic stem cells remarkably enhance cell fusion-mediated reprogramming with somatic cells in vitro, this mechanism may rescue injured DA neuron cells in PD. It has been argued that ASCs plasticity may be exploited clinically for cell replacement and/or gene therapy. However, only after there is a better understanding of the mechanisms involved and of the cells required for this differentiation, it will be possible to fully harness ASCs plasticity for clinical purposes. Thereby, in this project, we proposed to verify the cell fusion-mediated reprogramming mechanism in response to disease and tissue injury. Specifically, we aimed to determine whether this mechanism is relevant for tissue regeneration. We wanted to determine whether perturbation of the BMSCs controls and enhances in vivo reprogramming of possible fusion events formed in response to neurodegeneration.

In our project, we transplanted perturbed or non-perturbed BMSCs into adult mouse brain. We observed a high amount of fusion cells in mouse brain close to the transplanted region. To assess short- and long-term regeneration, transplanted cells, were evaluated for reprogramming, differentiation or trans-differentiation at different time points post-transplantation. By four weeks after transplantation, tyrosine-hydroxylase positive axons were detected close to the graft site. Additionally, to analyse rescue of the PD phenotype after BMSCs transplantation, we performed several neurobehavioural tests of motor disability 3, 14, 21 days and 1 month after cell grafting. In parallel, assessment of cellular recovery by stereological analysis demonstrated up to a 50 - 55 % loss of dopamine neurons in the substantia nigra pars compacta (SNpc) in mice following MPTP treatment, compared with saline-treated animals. Interestingly, in the MPTP treated mice grafted with BMSCs, there was only a 15 - 20 % MPTP-induced loss of dopamine neurons.

Potential impact.

We believe that the cell fusion-mediated reprogramming mechanism could lead to the development of a radically new therapy for several neurodegenerative diseases that currently lack effective treatments. The ready access to bone marrow-derived stem cells through bone marrow aspirates, mobilised peripheral blood, or umbilical cords, together with the possibility to direct adult hematopoietic stem cells to differentiate into neuronal cells will have a tremendous impact on regenerative medicine. However, this mechanism is also attractive to several fields in health and life science outside neurodegenerative diseases (e.g. cardiovascular and endocrine diseases). Thus, it is crucial to have solid scientific understanding of this mechanism in order to be successfully translated to a new clinical treatment. This field is still in its infancy and a more of experimentation and optimisation is needed.