Abstract
During the maturation of intestinal epithelial cells along the crypt/surface axis, a multitude of acid/base transporters are differentially expressed in their apical and basolateral membranes, enabling processes of electrolyte, macromolecule, nutrient, acid/base and fluid secretion, and absorption. An intracellular pH (pHi)-gradient is generated along the epithelial crypt/surface axis, either as a consequence of the sum of the ion transport activities or as a distinctly regulated entity. While the role of pHi on proliferation, migration, and tumorigenesis has been explored in cancer cells for some time, emerging evidence suggests an important role of the pHi in the intestinal stem cells (ISCs) proliferative rate under physiological conditions. The present review highlights the current state of knowledge about the potential regulatory role of pHi on intestinal proliferation and differentiation.
Highlights
Mechanisms of acid/base control in the gastrointestinal tract came into focus a century ago, because during the decades of very high gastric ulcer prevalence, a relationship between peptic ulcers and gastric acidity had been recognized (Banic et al, 2011)
PHi in Intestinal Epithelial Proliferation is counteracted by the apical acid extruders, the Na+/H+ exchangers NHE2, NHE3, and NHE8 (SLC9A2/3/8); a process that results in salt and water absorption
Employing an array of sophisticated methods, the group demonstrated an expression and functional activity of cystic fibrosis transmembrane conductance regulator (CFTR) in murine intestinal stem cells (ISCs), an alkaline intracellular pHi in Cftr−/− ISCs, accompanied by hyperproliferation in Cftr−/− organoids. These findings suggest that the Cftr−/−-associated crypt and villus elongations, which are observed in the absence of inflammatory markers (Tan et al, 2020) and the hyperproliferation described in murine Cftr−/− intestinal epithelium (Gallagher and Gottlieb, 2001) may be partially a consequence of the lack of CFTR in ISCs
Summary
Mechanisms of acid/base control in the gastrointestinal tract came into focus a century ago, because during the decades of very high gastric ulcer prevalence, a relationship between peptic ulcers and gastric acidity had been recognized (Banic et al, 2011). These findings suggest that the Cftr−/−-associated crypt and villus elongations, which are observed in the absence of inflammatory markers (Tan et al, 2020) and the hyperproliferation described in murine Cftr−/− intestinal epithelium (Gallagher and Gottlieb, 2001) may be partially a consequence of the lack of CFTR in ISCs. Crossbreeding of Cftr−/− and wt mice with transgenic mice which express a fluorophore (EGFP)-labeled WNT transducer Disheveled (Dsv) and the cell membrane-targeted, two-color fluorescent Cre-reporter RosaTmT/mG enabled the group to study the proximity of Dsv to the membrane receptor Frizzled 7, which has been recognized as a key event in WNT signaling (Axelrod, 2001) in Cftr−/− and wt ISCs with live cell imaging.
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