Proliferation, not apoptosis, alters epithelial cell migration in small intestine of CFTR null mice

Abstract

Expression of a mutated cystic fibrosis transmembrane conductance regulator (CFTR) has been shown to enhance proliferation within CF airways, and cells expressing a mutated CFTR have been shown to be less susceptible to apoptosis. Because the CFTR is expressed in the epithelial cells lining the gastrointestinal tract and all CF mouse models are characterized by gastrointestinal obstruction, we hypothesized that CFTR null mice would have increased epithelial cell proliferation and reduced apoptosis within the small intestine. The rate of intestinal epithelial cell migration from crypt to villus was increased in CFTR null mice relative to mice expressing the wild-type CFTR. This difference in migration could be explained by an increase in epithelial cell proliferation but not by a difference in apoptosis within the crypts of Lieberkühn. In addition, using two independent sets of CF cell lines, we found that epithelial cell susceptibility to apoptosis was unrelated to the presence of a functional CFTR. Thus increased proliferation but not alterations in apoptosis within epithelial cells might contribute to the pathophysiology of CF.

Reduced NHE3-mediated Na+ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice

“…The intestinal tract of CF mice is known to exhibit a number of histological abnormalities, including goblet cell hyperplasia, accumulation of eosinophilic granules in the crypt lumen (5,24), and increased proliferation of crypt cells (18). Goblet cell hyperplasia in the villi was apparent in Cftr Ϫ/Ϫ Nhe3 ϩ/ϩ mice, as expected, but this phenotype was eliminated in CF mice …”

“…The effects of Nhe3 ablation on increased cell proliferation in the crypts of CF mice (18) were less clear. Nhe3-null mice exhibited an increase in cell proliferation that was similar in magnitude to that of CF mice, but when combined with the Cftr-null background the absence of both Nhe3 alleles appeared to have a moderating effect on this aspect of the phenotype.…”

“…CF mice develop goblet cell hyperplasia and inflammation of the intestine (42,54), which contribute to the disease process. They also have impaired innate immunity due to the failure of Paneth cell granules to dissolve in the crypts of the small intestine (5), and the crypts show an abnormally high proliferative capacity (18).…”

Functional Cftr in crypt epithelium of organotypic enteroid cultures from murine small intestine

“…An alkaline pH i in Cftr-deficient epithelium would negatively impact processes of apoptosis by diminishing cellular activity of acid endonucleases (5) and positively influence cell proliferation by facilitating G 2 /M transition in the cell cycle and enhancing membrane biogenesis (47,64). Previous studies (19) have shown that Cftr KO mice exhibit hyperproliferation of the intestinal epithelium, and it is known that cystic fibrosis patients have an approximately six-fold risk of gastrointestinal neoplasia despite being a relative young population (41). Thus the alkaline pH i in CF crypt epithelium may be a potential contributor to the propensity for gastrointestinal cancer in CF patients.…”

CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation via the ZONAB pathway

“…Interestingly, a potential link between CFTR and epithelial cell polarization has previously been proposed (Hollande et al, 1998) but the underlying mechanism remained unclear. In addition, increased proliferative activity was observed in intestinal crypt epithelial cells of CFTR-null mice (Gallagher and Gottlieb, 2001). The present work, together with these previous studies, indicates the possible role of CFTR in the control of proliferation and differentiation through modulation of the ZONAB pathway in several tissues.…”