Enterocyte expression of epidermal growth factor receptor is not required for intestinal adaptation in response to massive small bowel resection

Abstract

Purpose Intestinal adaptation following massive small bowel resection (SBR) permits improved absorption of enteral nutrition despite significant loss of bowel length. Epidermal growth factor (EGF) and its receptor (EGFR) have previously been established to play major roles in the pathogenesis of adaptation. This study tested the hypothesis that EGFR signaling within the epithelial cell compartment (enterocytes) is required for intestinal adaptation. Methods We developed a tamoxifen-inducible Villin-Cre/LoxP recombinant system for enterocyte-directed EGFR deletion using EGFR-floxed mice. EGFR-null mice and wild type (WT) littermates underwent either 50% proximal SBR or sham operation. Ileal tissue was harvested on post-operative day 7. To assess for adaptation, villus height and crypt depth as well as rates of crypt cell proliferation and apoptosis were measured. Results Adaptation after SBR occurred normally, as demonstrated by significant increases in villus height, crypt depth, crypt proliferative and apoptotic index in both the WT and EGFR-null mice. Conclusion Enterocyte EGFR expression is not required for the adaptation response to massive SBR. This novel finding suggests that enterocyte proliferation during adaptation is regulated by EGFR signaling in cells other than enterocytes, perhaps within the mesenchymal cell compartment of the bowel wall via factor(s) that are presently unknown.

Loss of ADAM17-Mediated Tumor Necrosis Factor Alpha Signaling in Intestinal Cells Attenuates Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

“…Under normal physiological conditions, adult IEC-Adam17 KO mice are overtly normal and show no significant changes in crypt-villus architecture, crypt proliferation and EBF. This finding is consistent with the lack of intestinal phenotype observed in different IEC-specific EGFR/ErbB-deficient mice (44,45). Moreover, the normal secretory differentiation and viability of IEC-Adam17 KO mice suggests that ADAM17 is not essential for Notch signaling in IECs (37).…”

“…Taken together, these results indicate that IEC-Adam17 KO mouse model is a suitable model to investigate the contribution of ADAM17 signaling from IECs under different experimental conditions. IEC proliferation is critical for adaptive growth after intestinal injury/inflammation (47,48), and EGFR/ErbB is a major mediator of these IEC responses (44,48,49). In the DSS colitis model, hypomorphic Egfr mice and ErbB ligand-deficient mice display exacerbated intestinal inflammation (50,51), whereas more recent studies using different IEC-ErbB KO mice have shown that all four ErbB receptors contribute, in various degrees, to protection against DSS-induced colitis (19,24,26,45).…”

Insulin-like growth factor 2 and its enterocyte receptor are not required for adaptation in response to massive small bowel resection

“…As such, it is possible that intestinal mucosal growth is driven by IGF1R stimulation of subepithelial mesenchymal or immune cells. This paradigm is similar to our findings of impaired resection-induced adaptation responses under multiple conditions of global inhibition of epidermal growth factor receptor (EGFR) signaling [28] but preserved responses in mice with genetically disrupted expression of intestinal epithelial EGFR [29]. …”

Mechanisms of intestinal adaptation

“…The adaptive response is completely blocked in these mice [52]. However, the mechanism by which EGF results in an increased adaptive response remains unclear, as subsequent analyses have shown that the gut-epithelial specific knockout of the EGF receptor does not block the adaptive response [53]. …”