Bile canaliculi formation in primary hepatocytes requires α1β1 integrin-dependent adherens junction re-organization.

Hepatocytes, the parenchymal cells of the liver, exhibit a unique epithelial polarity phenotype in which their bile canaliculi-forming luminal domains and underlying F-actin-linked cell-cell adhesion belt organize not parallel but perpendicular to their basal extracellular matrix (ECM)-contacting domains. Hepatocytes also differ from other epithelia in that they form two basal domains on opposite sites, face only a sparse ECM and express mesenchymal rather than epithelial-typical integrins. What role these hepatocyte-specific cell-ECM interactions play in the establishment and maintenance of the unique hepatocyte polarity phenotype is unknown. We report that in primary rat hepatocyte cultures, development and maintenance of a bile canaliculi network requires the repression of contractile substrate-parallel cell-cell adhesions near matrix-contacting sites. This occurs only when cells contact ECM at two sites; it requires the integrin α1β1, and on rigid matrix, additionally an αV-integrin. We furthermore found that low matrix rigidity, as characteristic of the healthy liver, favors bile canaliculi formation, which becomes independent of p120 catenin-dependent adherens junctions. Our findings thus link the unique hepatocyte polarity phenotype to adherens junction formation downstream of their unique ECM and integrin makeup.