Transforming Growth Factor β Controls the Directional Migration of Hepatocyte Cohorts by Modulating Their Adhesion to Fibronectin

Abstract

Transforming growth factor ␤ (TGF-␤) has a strong impact on liver development and physiopathology, exercised through its pleiotropic effects on growth, differentiation, survival, and migration. When exposed to TGF-␤, the mhAT3F cells, immortalized, highly differentiated hepatocytes, maintained their epithelial morphology and underwent dramatic alterations of adhesion, leading to partial or complete detachment from a culture plate, followed by readhesion and spreading. These alterations of adhesive behavior were caused by sequential changes in expression of the ␣5␤1 integrin and of its ligand, the fibronectin. The altered specificity of anchorage to the extracellular matrix gave rise to changes in cells' collective motility: cohorts adhering to fibronectin maintained a persistent, directional motility, with ezrin-rich pathfinder cells protruding from the tips of the cohorts. The absence of adhesion to fibronectin prevented the appearance of polarized pathfinders and lead to random, oscillatory motility. Our data suggest a novel role for TGF-␤ in the control of collective migration of epithelial cohorts. INTRODUCTIONThe cytokines of the transforming growth factor ␤ (TGF-␤) family have essential and pleiotropic roles in embryonic development, adult homeostasis, and pathology (reviewed in Massague et al., 2000;Bachman and Park, 2005). Although the outcome of the TGF-␤ signaling is strongly dependent on its cross-talk with other signal transduction pathways, as a general rule it is cytostatic and cytotoxic for epithelia and the immune system, while it stimulates differentiation and migration of endothelial and mesenchymal cells (Siegel and Massague, 2003).Liver is one of the organs dramatically affected by the TGF-␤ signaling (reviewed in Bissell et al., 2001). Ectopic expression of the active form of TGF-␤1 gives rise to liver fibrosis through the differentiation of hepatic stellate cells into myofibroblasts and stimulation of collagen synthesis and deposition (Sanderson et al., 1995). During liver regeneration, TGF-␤ acts to control the transient stimulation of stellate cells and, through its growth inhibitory action on hepatocytes, the extent of hepatocyte regenerative proliferation (Romero-Gallo et al., 2005). Primary hepatocytes in culture are also sensitive to TGF-␤: in this setting the cytokine provokes a strong apoptotic response of both mature and fetal hepatocytes (Fabregat et al., 1996;Gressner et al., 1997), whereas early hepatic precursors survive the same treatment . The resistance to the apoptotic effects of TGF-␤ signaling can be achieved by simultaneous activation of MAPK Erk and PI3K survival signaling (Fabregat et al., 1996;Janda et al., 2002;Valdes et al., 2004), which likely accounts for continued survival and proliferation of many hepatoma cell lines in the presence of TGF-␤ (Gressner et al., 1997). Cross-talk with other signal transduction pathways (Janda et al., 2002;Cordenonsi et al., 2003;Kamaraju and Roberts, 2005;Mishra et al., 2005;Katuri et al., 2006), acquisition of mutations invalidati...

Type XVIII collagen is essential for survival during acute liver injury in mice

“…Our analysis and previous literature suggests that these two integrins are highly expressed in the liver and particularly in hepatocytes (supplementary material Fig. S4) (Binamé et al, 2008; Pinkse et al, 2004). These integrins are also implicated in mediating survival signaling in epithelial cells (Howlett et al, 1995; Liu Tsang et al, 2007).…”

Cell shape and TGF‐β signaling define the choice of lineage during in vitro differentiation of mouse primary hepatic precursors

“…Changes in cell shape are classically governed by Rho GTPase signaling (reviewed in Binamé et al, 2010). While we detected no impact of RhoA or ROCK on the two types of organoids described here, it is of interest that BMEL cells cultured on top of a compliant layer of Matrigel organize into cohorts partially embedded in the matrix, whose organization differs from the fully embedded organoids described here, in particular in respect to localized Rac1 signaling (Biname et al, 2008).…”

Decreased Tumor Progression and Invasion by a Novel Anti-Cell Motility Target for Human Colorectal Carcinoma Cells

“…Depletion of this critical cytoskeletal linker was shown to decrease TGFβ and Ras/ERK signaling through novel mechanisms [4], [64], [65]. Further, mutations that affect Ezrin binding proteins have been shown to dominantly suppress both activation of TGFβ and FN production [63].…”

“…Various cellular events are known to be associated with this increased potential for malignant cells to spread to local and distant sites. Among these events are elevated expression or activity of signaling components and cellular scaffolds [2], [4]. However, a complete understanding of the highly integrated network of signaling pathways and complexes relevant to the cell migration and invasion process is still lacking and often depends on the tissue of origin, as well as on the precise combination of oncogenically active alterations that prevail.…”