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

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

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2-21
Number of pages20
JournalAmerican Journal of Stem Cells
Volume1
Issue number1
StatePublished - 2012

Keywords

  • Amyotrophic lateral sclerosis
  • Astroglia
  • Microglia
  • Motor neuron
  • Oxidative stress
  • Transplantation

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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