Control of hepatocyte morphology and function by the extracellular matrix

The interaction of mammalian cells with surfaces is central to a variety of fields including tissue engineering and mammalian cell bioreactors. The role of cell adhesion in regulating cell function was investigated by culturing hepatocytes, the major liver cell type, on surfaces coated with extracellular matrix (ECM) molecules. ECM molecules mediate cell adhesion and organization by binding to specific cell surface receptors. Hepatocytes exposed to dishes coated with a low density of ECM molecules $(<$50 fmol/cm$\sp2)$ attached, but did not spread extensively on the culture surface (projected cell area $<$2000 $\mu$m$\sp2).$ A high secretion rate for albumin (150 pg/cell/24 hr) and other proteins specifically synthesized by hepatocytes was maintained, and cells did not multiply. In contrast, hepatocytes cultured on a high density of ECM molecules $(>$1000 fmol/cm$\sp2)$ spread to greater than 5000 $\mu$m$\sp2,$ synthesized liver-specific proteins at much lower rates (e.g., albumin secretion decreased to 75 pg/cell/24 hr after 2 days), and multiplied. Further studies revealed that while the density of ECM adhesion sites controlled the relative rate of cell spreading, temporal changes in the cellular cytoskeleton following adhesion induced parallel changes in the spreading rate of cells. A quantitative model of the spreading process was then developed to allow prediction of spreading under given experimental conditions. These results suggest that cell function can be tightly regulated by controlling the ability of the cell adhesion surface to regulate changes in cell morphology, and these changes in cell morphology can be quantitatively studied and modeled. (Copies available exclusively from MIT Libraries, Rm. 14-0551, Cambridge, MA 02139-4307. Ph. 617-253-5668; Fax 617-253-1690.)