Regulation of intestinal epithelial cells transcriptome by enteric glial cells: impact on intestinal epithelial barrier functions

Abstract

BackgroundEmerging evidences suggest that enteric glial cells (EGC), a major constituent of the enteric nervous system (ENS), are key regulators of intestinal epithelial barrier (IEB) functions. Indeed EGC inhibit intestinal epithelial cells (IEC) proliferation and increase IEB paracellular permeability. However, the role of EGC on other important barrier functions and the signalling pathways involved in their effects are currently unknown. To achieve this goal, we aimed at identifying the impact of EGC upon IEC transcriptome by performing microarray studies.ResultsEGC induced significant changes in gene expression profiling of proliferating IEC after 24 hours of co-culture. 116 genes were identified as differentially expressed (70 up-regulated and 46 down-regulated) in IEC cultured with EGC compared to IEC cultured alone. By performing functional analysis of the 116 identified genes using Ingenuity Pathway Analysis, we showed that EGC induced a significant regulation of genes favoring both cell-to-cell and cell-to-matrix adhesion as well as cell differentiation. Consistently, functional studies showed that EGC induced a significant increase in cell adhesion. EGC also regulated genes involved in cell motility towards an enhancement of cell motility. In addition, EGC profoundly modulated expression of genes involved in cell proliferation and cell survival, although no clear functional trend could be identified. Finally, important genes involved in lipid and protein metabolism of epithelial cells were shown to be differentially regulated by EGC.ConclusionThis study reinforces the emerging concept that EGC have major protective effects upon the IEB. EGC have a profound impact upon IEC transcriptome and induce a shift in IEC phenotype towards increased cell adhesion and cell differentiation. This concept needs to be further validated under both physiological and pathophysiological conditions.

Novel functional roles for enteric glia in the gastrointestinal tract

“…Thus far, S-nitrosoglutathione, 16 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), 17 transforming growth factor (TGF)-β1 18 and proepidermal growth factor 19 have emerged as mucosal-glial-derived substances that influence gut epithelial cell differentiation, adhesion, migration and proliferation, apparently through actions on gene expression in the epithelial cell transcriptome (Figure 2b). 20 These findings-mainly from in vitro experiments assessing the effects of cultured glia on cultured epithelial cell monolayers-support the concept that mucosal enteric glia are a crucial component of the gut barrier by directing the maturation of epithelial cells.…”

Vagal nerve stimulation protects against burn-induced intestinal injury through activation of enteric glia cells

“…It is important to acknowledge that there may be other mechanisms by which stimulating the vagus nerve may protect against burn-induced gut injury. In addition to secreting GSNO, activated enteric glia cells cause numerous changes in gene transcription within the intestinal epithelial cell that may alter barrier function (23). Vagal nerve stimulation may also alter intestinal function after injury by other pathways including neuropeptide release.…”

S100B protein in the gut: The evidence for enteroglial-sustained intestinal inflammation

“…EGCs release a wide range of factors accounting for the development, survival and differentiation of peripheral neurons [27] . Traditionally, EGCs have been considered as a mechanical support for enteric neurons, but, in recent years, this restrictive view has changed to one of a more articulate and complex nature, since it has been described that EGCs are involved in the maintenance of intestinal homeostasis [28][29][30] . Indeed, EGCs control intestinal epithelial barrier (IEB) functions, as demonstrated in animal studies in which the ablation of enteroglial network enhances intestinal vascular permeability together with an increase in IEB paracellular permeability [31][32][33][34] .…”