UTILIZZO E CONFRONTO TRA CELLULE STAMINALI NEURONALI DI DIVERSA ORIGINE: EFFICACIA TERAPEUTICA IN UN MODELLO MURINO DI ATROFIA MUSCOLARE SPINALE

Spinal muscular atrophy (SMA), characterized by selective loss of lower motor neurons, is an incurable genetic neurodegenerative disease.and represents one of the most common genetic causes of infant mortality. Patients with SMA exhibit muscle weakness and hypotonia. Stem cell transplantation is a potential therapeutic strategy for SMA and other motor neuronal diseases. In this study, we analized the therapeutic capacity of different stem cells sources in order to improve SMA phenotype in a SMA murine model. First of all we isolated spinal cord neural stem cells (NSCs) from mice expressing green fluorescent protein (GFP) only in motor neurons and assessed their therapeutic effects on the phenotype of SMA mice. Intrathecally grafted NSCs migrated into the parenchyma and generated a small proportion of motor neurons. Treated SMA mice exhibited improved neuromuscular function, increased life span, and improved motor unit pathology NSC transplantation positively affected the SMA disease phenotype, indicating that transplantation of NSCs may be a possible treatment for SMA. However primary NSC as stem cell source have limited translational value. Thus we used alternative stem cells sources, NSC derived from wild-type embryonic stem cells (wt-ESCs) and from a drug-selectable embryonic stem cell line (OSG-ESC. This cells have promise as an unlimited source of NSCs for transplantation. We found that ESC-derived NSCs can differentiated into motor neuron in vitro, and, when intrathecally transplanted into SMA mice survived, migrated, ameliorated behavioral and life-span and may confer neuroprotection in SMA mice. NSCs obtained using a drug-selectable ESC line (positively for neuroepithelial cells and negatively for undifferentiated cells) yielded the greatest improvements. As with cells originating from primary tissue, the ESC-derived NSCs integrated appropriately into the parenchyma, expressing neuron- and motor neuron-specific markers. Our results suggest translational potential for the use of pluripotent cells in NSC-mediated therapies and highlight potential safety improvements and benefits of drug-selection for neuroepithelial cells.