Modulating the reactive phenotype of astrocytes in amyotrophic lateral sclerosis: the therapeutic effect of exosome-derived mesenchymal stem cells

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by degeneration and death of motor neurons (MNs). ALS is multifactorial and non-cell autonomous disease and astrocytes play a key role in this complex scenario. We previously demonstrated the beneficial outcome of intravenous administration of mesenchymal stem cells (MSCs) in the SOD1G93A mouse model of ALS and we postulated that MSCs produce their therapeutic effects via the modulation of the glial cell reactive phenotypes. We here studied the in-vitro activity of MSC-derived exosomes and their shuttled miRNAs on: SOD1G93A mouse-derived spinal cord astrocytes and on human inducible neuro progenitor cells (iNPCs)-derived astrocytes (iAstrocytes) differentiated from fibroblasts of ALS patients. The exposure of murine SOD1G93A astrocytes to MSCs-derived exosomes significantly reduced the astrogliosis, downregulated neuroinflammatory markers, restored the production of pro-inflammatory cytokines and increased the viability of SOD1G93A spinal motoneurons (MNs) co-cultured with exosome-treated astrocytes. Transfection with specific miRNA mimics, found to be upregulated in primed MSCs and validated in their secreted exosomes, significantly modulated the reactive and neuroinflammatory phenotype of astrocyte. By exploiting the iNPCs-derived astrocytes, as a human experimental model of ALS, we could also demonstrate that the in-vitro treatment of iAstrocytes with human MSC-derived exosomes activated the antioxidant axis and reduced the iAstrocyte-mediated MN toxicity. Our results suggest that MSC-derived exosomes and their miRNAs cargo, can modulate the neuroinflammatory and antioxidant pathways in reactive ALS-astrocytes. These effects have a positive impact on MN viability and pave the way for translational preclinical studies and clinical trial for ALS treatment.