Differentiated intestinal epithelial cells express high levels of TGF-β receptors and exhibit increased sensitivity to growth inhibition.
ABSTRACT Intestinal epithelial cells (IECs) within crypts continuously divide and differentiate as they migrate up towards the luminal surface of the mucosa. With the onset of differentiation, IECs lose their proliferative potential, but the exact mechanism remains unknown. This current study examined the involvement of the TGF-β signaling pathway in this process.
Studies were conducted in the IEC-6 cell line derived from rat small intestinal crypt cells. Cell differentiation was induced by forced expression of the Cdx2 gene, a transcription factor responsible for controlling intestinal epithelial cell differentiation.
Forced expression of the Cdx2 gene in stable Cdx2-transfected IEC-6 cells resulted in a differentiated phenotype as indicated by morphological features and increased expression of sucrase-isomaltase. Levels of TGF-β type I receptor (TGFβ-RI) and TGF-β type II receptor (TGFβ-RII) increased in these differentiated epithelial cells. The induced TGFβ-RI and TGFβ-RII expression in Cdx2-transfected IEC-6 cells was associated with increased sensitivity to TGF-β-induced growth inhibition. Depletion of cellular polyamines further increased TGF-β receptor expression and additionally enhanced the response to TGF-β-induced growth inhibition. Increased TGFβ-RI and RII in polyamine-deficient cells were also associated with an induction in JunD/AP-1 activity.
These results indicate that the loss of the proliferative potential in differentiated IECs results partially from the increased expression of TGF-β receptors.