ALPHA(3)BETA(1)-INTEGRIN AS A CRITICAL MEDIATOR OF THE HEPATIC DIFFERENTIATION RESPONSE TO THE EXTRACELLULAR-MATRIX

The extracellular matrix (ECM) promotes the differentiation of many ce ll types, and ECM remodeling in the liver has been implicated in embry onic development, tissue injury, and oncogenesis, Integrins are hetero dimeric ECM receptors that play critical roles in transducing the comp osition of the ECM in the cell environment. We previously showed that mouse H2.35 cells, a conditionally transformed, liver-derived cell lin e, assume a more differentiated hepatocyte morphology and enhanced liv er-specific gene expression when the cells are cultured on gelatinous ECM substrata. Here we show that H2.35 cells express relatively high l evels of alpha(3)beta(1)-integrins, similar to that previously shown f or immature hepatocytes, transformed hepatocytes, and biliary cells. H owever, the cell morphological responses that depend on alpha(3)beta(1 )-integrin have not been defined, We found that transfecting H2.35 cel ls with antisense RNA construct directed to alpha(3)-subunit messenger RNA perturbs the initial cell attachment to laminin and collagen, and strongly inhibits cell morphological, proliferative, and gene express ion responses to a collagen gel substratum, In situ hybridization to m ouse embryo tissues demonstrates the presence of alpha(3)-subunit mess enger RNAs in newly formed hepatocytes. We suggest that alpha(3)beta(1 )-integrins are important for immature and transformed hepatocytes to respond morphologically to the extracellular matrix.