The Fas/Fas ligand apoptosis pathway underlies immunomodulatory properties of human biliary tree stem/progenitor cells

J Hepatol. 2014 Nov;61(5):1097-105. doi: 10.1016/j.jhep.2014.06.016. Epub 2014 Jun 19.

Abstract

Background & aims: Human biliary tree stem/progenitor cells (hBTSCs) are multipotent epithelial stem cells, easily obtained from the biliary tree, with the potential for regenerative medicine in liver, biliary tree, and pancreas diseases. Recent reports indicate that human mesenchymal stem cells are able to modulate the T cell immune response. However, no information exists on the capabilities of hBTSCs to control the allogeneic response. The aims of this study were to evaluate FasL expression in hBTSCs, to study the in vitro interaction between hBTSCs and human lymphocytes, and the role of Fas/FasL modulation in inducing T cell apoptosis in hBTSCs/T cell co-cultures.

Methods: Fas and FasL expression were evaluated in situ and in vitro by immunofluorescence and western blotting. Co-cultures of hBTSCs with human leukocytes were used to analyze the influence of hBTSCs on lymphocytes activation and apoptosis.

Results: hBTSCs expressed HLA antigens and FasL in situ and in vitro. Western blot data demonstrated that hBTSCs constitutively expressed high levels of FasL that increased after co-culture with T cells. Confocal microscopy demonstrated that FasL expression was restricted to EpCAM(+)/LGR5(+) cells. FACS analysis of T cells co-cultured with hBTSCs indicated that hBTSCs were able to induce apoptosis in activated CD4(+) and CD8(+) T cell populations. Moreover, the Fas receptor appears to be more expressed in T cells co-cultured with hBTSCs than in resting T cells.

Conclusions: Our data suggest that hBTSCs could modulate the T cell response through the production of FasL, which influences the lymphocyte Fas/FasL pathway by inducing "premature" apoptosis in CD4(+) and CD8(+) T cells.

Keywords: Endodermal stem cells; FasL; Human biliary tree stem/progenitor cells (hBTSCs); Immune modulation; T cell apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / cytology
  • Adult Stem Cells / immunology
  • Adult Stem Cells / metabolism
  • Apoptosis / immunology
  • Biliary Tract / cytology*
  • Biliary Tract / immunology*
  • Biliary Tract / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology
  • Coculture Techniques
  • Fas Ligand Protein / metabolism*
  • Fetal Stem Cells / cytology
  • Fetal Stem Cells / immunology
  • Fetal Stem Cells / metabolism
  • Humans
  • Immunomodulation
  • Lymphocyte Activation
  • Multipotent Stem Cells / cytology*
  • Multipotent Stem Cells / immunology*
  • Multipotent Stem Cells / metabolism
  • Signal Transduction
  • fas Receptor / metabolism*

Substances

  • FAS protein, human
  • FASLG protein, human
  • Fas Ligand Protein
  • fas Receptor