Submitted on June 16, 2005
Accepted on January 14, 2006
ENTERIC GLIA INHIBITS INTESTINAL EPITHELIAL CELL PROLIFERATION PARTLY THROUGH A TGF-
1-DEPENDENT PATHWAY
Michel Neunlist1*, Philippe Aubert1, Stepahnie Bonnaud2, Laurianne Van Landeghem1, Emmanuel Coron1, Thilo Wedel3, Philippe Naveilhan4, Anne Ruhl5, Bernard Lardeux1, Tor Savidge6, Francois Paris2, and Jean Paul Galmiche1
1 INSERM U539, IMAD, University of Nantes, Nantes, France
2 INSERM U601, Nantes, France
3 Department of Anatomy, University of Luebeck, Luebeck, Germany
4 INSERM U643, Nantes, France
5 Department of Human Biology, Technical University of Munich, Freising, Germany
6 Department of Gastroenterology, University of Texas Medical Branch, Galveston, TX, USA
* To whom correspondence should be addressed. E-mail: michel.neunlist{at}univ-nantes.fr.
Although recent studies have shown that enteric neurons control intestinal barrier function, the role of enteric glial cells (EGC) in this control remains unknown. Therefore, our goal was to characterize the role of EGC in the control of intestinal epithelial cell proliferation using an in vivo transgenic and an in vitro co-culture model. Assessment of intestinal epithelial cell proliferation following ablation of EGC in transgenic mice demonstrated a significant increase in crypt cell hyperplasia. Furthermore, mucosal glial network (assessed by immunohistochemical detection of S100-
) is altered in colon adenocarcinoma as compared to control tissue. In an in vitro co-culture model of subconfluent Caco-2 cells seeded onto Transwell filters with EGC, Caco-2 cell density and 3H-thymidine incorporation was significantly lower than in control (Caco-2 cultured alone). Flow cytometry analysis showed that EGC had no effect on Caco-2 cell viability. EGC induced a significant increase in Caco-2 cell surface area without any sign of cellular hypertrophy. These effects of EGC were also seen in various transformed or non-transformed intestinal epithelial cell lines. Furthermore, TGF-1 mRNA was expressed and TGF-1 was secreted by EGC. Exogenously added TGF-1 reproduced partly the EGC-mediated effects on cell density and surface area. In addition, EGC effects upon Caco-2 cell density were significantly reduced by a neutralizing TGF- antibody. In conclusion, EGC have profound anti-proliferative effects upon intestinal epithelial cells. Functional alterations in EGC may therefore modify intestinal barrier functions and be involved in pathologies such as cancer or inflammatory bowel diseases.
