Stem Cell Select

The stem cell field is gradually moving toward translational applications as exemplified by the papers highlighted in this Stem Cell Select. In vitro human embryonic stem cell (hESC) models of disease may prove useful for drug screening. Resolving whether cancer stem cells are important for the pathogenesis of all or only some human cancers should accelerate development of new stem cell-specific therapeutic strategies. Finally, visualizing how hematopoietic stem cell grafts colonize bone marrow in real time will provide insights enabling optimization of transplant protocols. The pathogenesis of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex. However, genetic evidence implicates mutations in the gene encoding superoxide dismutase (SOD1)—an enzyme that breaks down toxic free radicals—as contributing to the selective death of motor neurons. Animal models of ALS have shown that once the motor neurons are damaged and the disease process triggered, then disease progression depends on nonneuronal cells such as astrocytes, which are thought to be crucial mediators of mutant SOD1 toxicity. Now, the Gage and Eggan groups (Marchetto et al., 2008; Di Giorgio et al., 2008) present in vitro models of human ALS comprising motor neurons derived from hESCs cultured with astrocytes expressing either mutant or wild-type SOD1. Marchetto et al. (2008) grew hESC-derived motor neurons together with primary human astrocytes expressing either wild-type or mutant SOD1 (SOD1 G37R) and labeled the motor neurons using a lentivirus-Hb9::GFP construct. In their assay, Di Giorgio and colleagues generated an Hb9::GFP trans-genic hESC line, which they induced to form motor neurons that were then cocultured with primary astrocytes derived from either SOD1 G93A transgenic or control mice. Both groups found that when cocultured with astrocytes expressing mutant SOD1 (but not normal SOD1), the number of motor neurons decreased by $50%; coculture with fibroblasts expressing mutant SOD1 did not result in motor neuron death. Marchetto et al. then found that a greater number of mutant astrocytes were activated compared with control astrocytes. Activated astrocytes are part of the inflammatory response, and SOD1 G37R mutant astrocytes were found to boost production of reactive oxygen species (ROS), iNOS, NOX2, and CHGA, a neurosecre-tory protein that interacts specifically with mutant SOD1. These authors then screened antioxidant compounds in the cocul-ture system and found that the NOX2 inhibitor apocynin and the antioxidant a-lipoic acid decreased ROS generation. They further demonstrated that apocynin could abrogate death of motor neurons cocultured with SOD1 G37R astrocytes. Di Giorgio and colleagues …