Enteric glia inhibit intestinal epithelial cell proliferation partly through a TGF-β₁-dependent pathway

Abstract

Although recent studies have shown that enteric neurons control intestinal barrier function, the role of enteric glial cells (EGCs) in this control remains unknown. Therefore, our goal was to characterize the role of EGCs in the control of intestinal epithelial cell proliferation using an in vivo transgenic and an in vitro coculture model. Assessment of intestinal epithelial cell proliferation after ablation of EGCs in transgenic mice demonstrated a significant increase in crypt cell hyperplasia. Furthermore, mucosal glial network (assessed by immunohistochemical detection of S-100beta) is altered in colon adenocarcinoma compared with control tissue. In an in vitro coculture model of subconfluent Caco-2 cells seeded onto Transwell filters with EGCs, Caco-2 cell density and [3H]thymidine incorporation were significantly lower than in control (Caco-2 cultured alone). Flow cytometry analysis showed that EGCs had no effect on Caco-2 cell viability. EGCs induced a significant increase in Caco-2 cell surface area without any sign of cellular hypertrophy. These effects by EGCs were also seen in various transformed or nontransformed intestinal epithelial cell lines. Furthermore, TGF-beta1 mRNA was expressed, and TGF-beta1 was secreted by EGCs. Exogenously added TGF-beta1 reproduced partly the EGC-mediated effects on cell density and surface area. In addition, EGC effects on Caco-2 cell density were significantly reduced by a neutralizing TGF-beta antibody. In conclusion, EGCs have profound antiproliferative effects on intestinal epithelial cells. Functional alterations in EGCs may therefore modify intestinal barrier functions and be involved in pathologies such as cancer or inflammatory bowel diseases.

Histomorphometric study of role of lactoferrin in atrophy of the intestinal mucosa of rats

“…Similar results were obtained by Wang et al [38] in his study of pigs supplemented with 1 g/kg lactoferrin. Although, the villi in group CL are only slightly longer than villi of group Ci, without statistical significance, this result proves more consistent with the findings from the literature, which clearly demonstrates that there are highly effective mechanisms for maintaining the homeostasis of the intestinal epithelium [28][29][30]. The same is valid, therefore, when comparing the depth of the crypts in these two groups and also, in groups CL and SL, which showed no difference in crypt depth, even though the villus height was significantly higher in group CL.…”

“…However, in an experiment using cultures of various strains of intestinal cells, Goke et al [29] demonstrated that differentiated fibroblasts (myofibroblasts) often present in these culture models, regulate cell proliferation by paracrine action. More recently, Neunlist et al [30], also in an in vitro experiment have shown that neuronal and glial components of the enteric nervous system, particularly the glial cells, could act together with other components of the mucosa, such as myofibroblasts, to enhance the control over cell proliferation in the intestinal epithelium and contribute to the maintenance of homeostasis.…”

“…These cells are also considered important in the mechanism coordinating the crypt-villus unit. It is believed that the pericrypt myofibroblasts, which form a sheet underlying the intestinal epithelium, may modulate intestinal epithelial cell proliferation and differentiation, increase the resistance of lumen-blood barrier and modulate epithelial secretory responses to various agonists, such as acetylcholine or prostaglandins [30]. Shao and Sheng [43], in an experiment with mice, have demonstrated the important role of subepithelial myofibroblasts in regulating the composition of the microenvironment for regeneration of the intestinal epithelium, showing that on receiving extracellular stimuli, these cells produce a variety of epidermal growth factors, including amphiregulin (Areg), which stimulate the growth of intestinal epithelium through a paracrine pathway.…”

Le système nerveux entérique et l’unité neuro-glio-épithéliale digestive

“…Le concept d'UNGE s'est développé récemment sur la base de données anatomiques montrant : -1) l'existence d'une importante innervation de la BEI composée d'axones et de cellules gliales, chaque villus étant innervé par 70-92 neurones sous-muqueux chez le cobaye (Song et al 1995) et -2) la proximité étroite entre les fibres nerveuses et les CEI, séparées uniquement par la lame basale dont l'épaisseur est de l'ordre du micromètre (Neunlist et al 2007 ;Van Landeghem et al 2011).…”

“…Enfin, les CGE jouent un rôle majeur dans le contrôle de la prolifération des CEI. Ainsi, les CGE inhibent la prolifération des CEI par la libération du transforming growth factor ␤1 (TGF ␤1) ou de la 15-deoxy-12,14-prostaglandine J2 (15dPGJ2) (Neunlist et al 2007 ;Bach-Ngohou et al2010). D'autre part, l'ablation des CGE in vivo conduit à une hyperplasie des cryptes et une hyper-prolifération des CEI.…”