Fas Activation Increases Neural Progenitor Cell Survival

J Neurosci Res. 2010 Mar;88(4):746-57. doi: 10.1002/jnr.22253.

Abstract

Although there is a sizable amount of research focusing on adult neural progenitor cells (NPCs) as a therapeutic approach for many neurodegenerative diseases, including multiple sclerosis, little is known about the pathways that govern NPC survival and apoptosis. Fas, a member of the death receptor superfamily, plays a well-characterized role in the immune system, but its function in neural stem cells remains uncertain. Our study focuses on the effects of Fas on NPC survival in vitro. Activation of Fas by recombinant Fas ligand (FasL) did not induce apoptosis in murine NPCs in culture. In fact, both an increase in the amount of viable cells and a decrease in apoptotic and dying cells were observed with FasL treatment. Our data indicate that FasL-mediated adult NPC neuroprotection is characterized by a reduction in apoptosis, but not increased proliferation. Further investigation of this effect revealed that the antiapoptotic effects of FasL are mediated by the up-regulation of Birc3, an inhibitor of apoptosis protein (IAP). Conversely, the observed effect is not the result of altered caspase activation or FLIP (Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein) up-regulation, which is known to inhibit caspase-8-mediated cell death in T cells. Our data indicate that murine adult NPCs are resistant to FasL-induced cell death. Activation of Fas increased cell survival by decreasing apoptosis through Birc3 up-regulation. These results describe a novel pathway involved in NPC survival.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Brain / cytology
  • Bromodeoxyuridine / metabolism
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Fas Ligand Protein / pharmacology
  • Fibroblast Growth Factors / pharmacology
  • Flow Cytometry / methods
  • In Situ Nick-End Labeling / methods
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Neurons / metabolism*
  • Stem Cells / physiology*
  • Time Factors
  • Ubiquitin-Protein Ligases
  • fas Receptor / metabolism*

Substances

  • Fas Ligand Protein
  • Fas protein, mouse
  • Inhibitor of Apoptosis Proteins
  • fas Receptor
  • Fibroblast Growth Factors
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Birc3 protein, mouse
  • Ubiquitin-Protein Ligases
  • Bromodeoxyuridine