MULTIFACETED REGULATION OF CELL-DIFFERENTIATION BY EXTRACELLULAR-MATRIX

Extracellular matrix (ECM) is an intricate network composed of an arra y of macromolecules, the importance of which is becoming increasingly apparent. The ECM is an integral part of the machinery that regulates cell function; its role in cell differentiation and tissue-specific ge ne expression, although essential, is not yet understood. It can act a s a positive as well as a negative regulator of functional differentia tion depending on the cell type and the genes studied. It also acts in a hierarchical fashion, exacting higher and higher degrees of stringe ncy to achieve full functional differentiation. Regulation by ECM is c losely interrelated with the action of other regulators of cellular fu nction, such as growth factors and hormones. But ECM may exert its reg ulation of gene expression by mechanisms distinct from those known for soluble transcription factors. In this short review, we describe thre e systems in which ECM has been shown to play a crucial role in functi onal differentiation, but we emphasize mainly the work from our own la boratory to provide a more in-depth analysis of one system. The three systems are: mouse mammary epithelial cells, rat hepatocytes, and huma n keratinocytes. The crucial role of ECM in normal cell differentiatio n implies that its alteration may have serious consequences in maligna ncies and other diseases. The current functional cell culture models c ould provide powerful tools not only for understanding regulation of n ormal cell function but also for the studies of tumorigenesis and poss ibly cancer therapy.