Amyotrophic lateral sclerosis (ALS) is a fatal incurable neurodegenerative disease characterized by progressive degeneration of motor neurons (MNs), leading to relentless muscle paralysis. In the early stage of the disease, MN loss and consequent muscle denervation are compensated by axonal sprouting and reinnervation by the remaining MNs, but this mechanism is insufficient in the long term. Here, we demonstrate that induced pluripotent stem cell-derived neural stem cells (NSCs), in particular the subpopulation positive for LewisX-CXCR4-β1-integrin, enhance neuronal survival and axonal growth of human ALS-derived MNs co-cultured with toxic ALS astrocytes, acting on both autonomous and non-autonomous ALS disease features. Transplantation of this NSC fraction into transgenic SOD1G93A ALS mice protects MNs in vivo, promoting their ability to maintain neuromuscular junction integrity, inducing novel axonal sprouting and reducing macro- and microgliosis. These effects result in a significant increase in survival and an improved neuromuscular phenotype in transplanted SOD1G93A mice. Our findings suggest that effective protection of MN functional innervation can be achieved by modulation of multiple dysregulated cellular and molecular pathways in both MNs and glial cells. These pathways must be considered in designing therapeutic strategies for ALS patients.

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