Am J Stem Cell 2012;2(1):2-21

Original Article
Mutant SOD1 microglia-generated nitroxidative stress promotes toxicity to human
fetal neural stem cell-derived motor neurons through direct damage and noxious
interactions with astrocytes  

Jason R. Thonhoff, Junling Gao, Tiffany J. Dunn, Luis Ojeda, Ping Wu

Department of Neuroscience and Cell Biology, Department of Biochemistry and Molecular Biology, University of Texas Medical Branch,
Galveston, Texas 77555, USA.

Received August 10, 2011; accepted August 18, 2011; Epub August 19, 2011; published January 1, 2012

Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. Human neural stem cells (hNSCs) may have the
potential to replace lost motor neurons. The therapeutic efficacy of stem cell therapy depends greatly on the survival of grafted stem
cell-derived motor neurons in the microenvironment of the spinal cord in ALS. After transplantation of hNSCs into the spinal cords of
transgenic ALS rats, morphological analysis reveals that grafted hNSCs differentiate into motor neurons. However, hNSCs degenerate
and show signs of nitroxidative damage at the disease end-stage. Using an in vitro coculture system, we systematically assess
interactions between microglia and astroglia derived from both nontransgenic rats and transgenic rats expressing human mutant
SOD1G93A before and after symptomatic disease onset, and determine the effects of such microglia-astroglia interactions on the
survival of hNSC-derived motor neurons. We found that ALS microglia, specifically isolated after symptomatic disease onset, are directly
toxic to hNSC-derived motor neurons. Furthermore, nontransgenic astrocytes not only lose their protective role in hNSC-derived motor
neuron survival in vitro, but also exhibit toxic features when cocultured with mutant SOD1G93A microglia. Using inhibitors of inducible
nitric oxide synthase and NADPH oxidase, we show that microglia-generated nitric oxide and superoxide partially contribute to motor
neuron loss and astrocyte dysfunction in this coculture paradigm. In summary, reactive oxygen/nitrogen species released from
overactivated microglia in ALS directly eliminate human neural stem cell-derived motor neurons and reduce the neuroprotective
capacities of astrocytes. (AJSC1108002).

Keywords: Amyotrophic lateral sclerosis, microglia, astroglia, motor neuron, transplantation, oxidative stress

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Address all correspondence to:
Ping Wu, MD, PhD
Department of Neuroscience and Cell Biology
University of Texas Medical Branch
Galveston, TX 77555-0620
Tel: 409-772-9858
Fax: 409-747-2200
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