EGF suppresses intestinal epithelial cell shedding both in vitro and in vivo via a MEK/ERK dependent pathway

Abstract

Epithelial cell shedding from the intestinal villus is a key element of normal tissue turnover. Increased cell shedding is associated with inflammatory bowel diseases. The signals regulating this process are not well understood. In this study, we asked whether shedding is controlled by epidermal growth factor (EGF) receptor, an important driver of intestinal growth and differentiation.METHODSCell extrusion events in vivo (zebrafish midgut) or in vitro (MDCK or IEC‐6 cells) were identified by rhodamine‐phalloidin labeling of condensed actin rings. In vitro, shedding rates were assessed by counting extruded cells in the culture media over time. EGF, with or without MEK inhibitor (U0126), was given by intraperitoneal injection (fish) or in culture media (cells).RESULTSEGF reduced detectable shedding events on zebrafish villi (34% decrease, p<0.05) and from MDCK (49% decrease, p<0.01) or IEC‐6 (42% decrease, p<0.01) cell monolayers. Pharmacological blockade of MEK/ERK reversed these effects both in vitro and in vivo. In contrast, inhibitors to other EGF‐stimulated pathways such as PI3K/Akt or PKC had no effect.CONCLUSIONSEGF receptor suppresses cell shedding in the intestinal epithelium through a specific MEK/ERK dependent pathway. These results may open the door to new therapeutic avenues for targeting excessive cell turnover in conditions such as inflammatory bowel diseases.