FAK Regulates Intestinal Epithelial Cell Survival and Proliferation during Mucosal Wound Healing

Abstract

BackgroundFollowing damage to the intestinal epithelium, restoration of epithelial barrier integrity is triggered by a robust proliferative response. In other tissues, focal adhesion kinase (FAK) regulates many of the cellular processes that are critical for epithelial homeostasis and restitution, including cell migration, proliferation and survival. However, few studies to date have determined how FAK contributes to mucosal wound healing in vivo.Methodology and Principal FindingsTo examine the role of FAK in intestinal epithelial homeostasis and during injury, we generated intestinal epithelium (IE)-specific conditional FAK knockout mice. Colitis was induced with dextran-sulfate-sodium (DSS) and intestinal tissues were analyzed by immunohistochemistry and immunoblotting. While intestinal development occurred normally in mice lacking FAK, FAK-deficient animals were profoundly susceptible to colitis. The loss of epithelial FAK resulted in elevated p53 expression and an increased sensitivity to apoptosis, coincident with a failure to upregulate epithelial cell proliferation. FAK has been reported to function as a mechanosensor, inducing cyclin D1 expression and promoting cell cycle progression under conditions in which tissue/matrix stiffness is increased. Collagen deposition, a hallmark of inflammatory injury resulting in increased tissue rigidity, was observed in control and FAK knockout mice during colitis. Despite this fibrotic response, the colonic epithelium in FAK-deficient mice exhibited significantly reduced cyclin D1 expression, suggesting that proliferation is uncoupled from fibrosis in the absence of FAK. In support of this hypothesis, proliferation of Caco-2 cells increased proportionally with matrix stiffness in vitro only under conditions of normal FAK expression; FAK depleted cells exhibited reduced proliferation concomitant with attenuated cyclin D1 expression.ConclusionsIn the colon, FAK functions as a regulator of epithelial cell survival and proliferation under conditions of mucosal injury and a mechanosensor of tissue compliance, inducing repair-driven proliferation in the colonic epithelium through upregulation of cyclin D1.

Heme modulates intestinal epithelial cell activation: involvement of NADPHox-derived ROS signaling

“…Although our data do not present robust evidences that link heme activation of FAK and heme-induced cell proliferation, a recent work elegantly described FAK as a crucial regulator of proliferation and restitution in epithelial injury conditions (24), highlighting the role of FAK on IE homeostasis.…”

High-mobility group box 1 promotes extracellular matrix synthesis and wound repair in human bronchial epithelial cells

“…Scratch wound healing in vitro occurs through migration of epithelial cells from the monolayer into the wound area and in part from proliferation of cells at the leading edge (46,70). Our experiments were not designed to dissect the relative contribution of migration vs. proliferation in HMGB1-exposed cultures, but HMGB1 does not appear to induce proliferation of lung epithelial cells in scratch wound assays (49), whereas several reports describe the capacity for HMGB1 to induce the migration of a number of different cell types (60,75).…”

C/EBP homologous protein inhibits tissue repair in response to gut injury and is inversely regulated with chronic inflammation

“…Consistently, recent studies demonstrate that mice carrying epithelial cell-specific modifications in genes implicated in cell proliferation and survival display delayed epithelial regeneration in response to acetic acidinduced ulceration, mechanical injury, and DSS treatment. [39][40][41] Although CHOP-induced defects in IEC proliferation might diminish the regenerative ability of the epithelial lining, epithelial integrity was maintained under non-challenged conditions. Noteworthy, CHOP can be posttranslationally modified by various kinases and does not possess a functional nuclear localization site, making nuclear translocation strongly dependent on heterodimer formation.…”