Applications for human neural stem cell-derived motor neurons in amyotrophic lateral sclerosis: Cell replacement therapy and disease modeling



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Amyotrophic lateral sclerosis (ALS) is an incurable neurological disease characterized by the selective degeneration of spinal and upper motor neurons. One approach in the development of therapies for ALS is to explore the potential of human fetal neural stem cells (hNSCs) to replace lost motor neurons. The therapeutic efficacy of stem cell transplantation would depend greatly on the survival of grafted stem cell-derived motor neurons in the microenvironment of the spinal cord in ALS. Previously, we reported that hNSCs could be instructed to differentiate into motor neurons both in vitro and in vivo. Here, we report that the transplantation of primed hNSCs into the spinal cords of transgenic ALS rats only slightly delayed disease progression. Morphological analyses of the transplantation sites revealed that the grafted hNSCs differentiated into motor neurons, but were degenerated and showed signs of nitroxidative damage at the disease end-stage. Using an in vitro coculture system, we provided evidence that human mutant SOD1(G93A)-expressing primary microglia, isolated after disease onset, were directly toxic to hNSC-derived motor neurons. Additionally, normal astrocytes not only lost their protective capacity toward hNSC-derived motor neuron survival in vitro, but also exhibited toxic features, when cocultured with mutant SOD1(G93A) microglia. Using inhibitors of inducible nitric oxide synthase and NADPH oxidase as well as scavengers for reactive oxygen and nitrogen species (ROS/RNS), we showed that microglia-generated nitric oxide, superoxide and peroxynitrite, at least, partially contributed to motor neuron loss and astrocyte dysfunction in this coculture paradigm. In summary, ROS/RNS released from overactivated microglia directly damage motor neurons and reduce the neuroprotective capacity of astrocytes, collectively dooming motor neuron survival in ALS. These data provide evidence that treating ALS with motor neuron cell-replacement therapies will not be efficacious unless the toxic milieu created by endogenous overactivated microglia in the spinal cord of ALS is dramatically altered. Outcomes from these studies should aid in the development of novel combined therapies using stem cells to treat patients with ALS.\r\n



transplantation, stem cell, oxidative stress, motor neuron, microglia, astrocyte, Amyotrophic lateral sclerosis