Embryonic stem cell–derived neural stem cells improve spinal muscular atrophy phenotype in mice

Spinal muscular atrophy (SMA), characterized by selective loss of lower motor neurons, is an incurable genetic neurological disease leading to infant mortality. We previously showed that primary neural stem cells (NSCs) derived from spinal cord can ameliorate the SMA phenotype in mice, but this primary source has limited translational value. Here, we show that pluripotent stem cells from embryonic stem cells (ESCs) show the same potential therapeutic effects as those derived from spinal cord and offer great promise as an unlimited source of NSCs for transplantation. We found that ESC-derived NSCs can differentiate into motor neurons in vitro and in vivo. In addition, following their intrathecal transplantation into SMA mice, the NSCs, like those derived from spinal cord, survived and migrated to appropriate areas, ameliorated behavioural endpoints and lifespan, and exhibited neuroprotective capability in SMA mice. NSCs obtained using a drug-selectable ESC line 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.