The effects of mechanical forces on intestinal physiology and pathology

Abstract

The epithelial and non-epithelial cells of the intestinal wall experience a myriad of physical forces including strain, shear, and villous motility during normal gut function. Pathologic conditions alter these forces, leading to changes in the biology of these cells. The responses of intestinal epithelial cells to forces vary with both the applied force and the extracellular matrix proteins with which the cells interact, with differing effects on proliferation, differentiation, and motility, and the regulation of these effects involves similar but distinctly different signal transduction mechanisms. Although normal epithelial cells respond to mechanical forces, malignant gastrointestinal epithelial cells also respond to forces, most notably by increased cell adhesion, a critical step in tumor metastasis. This review will focus on the phenomenon of mechanical forces influencing cell biology and the mechanisms by which the gut responds these forces in both the normal as well as pathophysiologic states when forces are altered. Although more is known about epithelial responses to force, information regarding mechanosensitivity of vascular, neural, and endocrine cells within the gut wall will also be discussed, as will, the mechanism by which forces can regulate epithelial tumor cell adhesion.

Fig 1

One possible pathway which regulates cell proliferation in response to strain on collagen. After PI3K is activated downstream in a Src-dependent fashion, the pathway diverges, and then re-converges on GSK. FAK, focal adhesion kinase; ERK, extracellular-related kinase; GSK, glycogen synthase kinase.

Fig 2

One possible pathway which regulates cell migration in response to strain on fibronectin. PI3K is phosphorylated in a Src-dependent manner that also requires Src-independnet phosphorylation of FAK at tyrosine-925. Although three arms of the pathway are depicted, all three are required for strain-induced migration. FAK, focal adhesion kinase; ERK, extracellular-related kinase; GSK, glycogen synthase kinase; MLC, myosin light-chain kinase.

Fig 3

One possible pathway in which pressure regulates cellular adhesion. The cytoskeleton plays a key role in transducing many of the relevant signals, but Src is activated independently of the cytoskeleton. Akt1 seems to aid in keeping FAK phosphorylated at the focal adhesion, though its role is complex and not completely understood. FAK, focal adhesion kinase; ILK, integrin-linked kinase.