Exosomes from mesenchymal stem cells: experimental assessment of an innovative therapeutic approach for ALS

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by progressive muscular paralysis and degeneration of motoneurons in the primary motor cortex, brainstem and spinal cord. Mutations in superoxide dismutase 1 (SOD1) gene are one of the genetic contributor to ALS. Therapeutic strategies for ALS are actually minimally effective on patients’ survival and quality of life. Stem cells represent a promising therapeutic approach in the treatment of neurodegenerative diseases and their beneficial effect seem to be due through a paracrine effect via the release of extracellular vesicles, in particular exosomes.In this doctoral thesis, I describe the studies to assess the neuroprotective effect of exosomes derived from syngeneic adipose stem cells (ASC) on in vitro and in vivo models of ALS, and the protocol for exosomes labeling to monitor the accumulation of exosomes after their in vivo administration.In in vitro experiments, the administration of ASC-exosomes after oxidative insult (H2O2) on motoneuron-like cell line (NSC-34) naïve and transfected with different human mutant SOD1 gene (G93A, G37R, A4V), protected cells from oxidative damage, with a significantly increase of cell viability. In in vivo experiments, the intravenous injection of ASC-exosomes in SOD1(G93A) mice at clinical onset until terminal stage point out that exosomes delay symptoms progression and postpone lifespan of treated animals. Our results demonstrate that ASC-exosomes have a neuroprotective effect in in vitro and in vivo models of ALS, indicating a possible new strategy as therapy in this neurodegenerative disease. Moreover, we set up a new protocol to label exosomes with superparamagnetic iron oxide nanoparticles, that allow to evaluate their tracking and their accumulation in vivo with a non-invasive technique, as magnetic resonance imaging.