Multi‐faceted regulation of cell differentiation by extracellular matrix

Abstract

Extracellular matrix (ECM) is an intricate network composed of an array 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 gene expression, although essential, is not yet understood. It can act as a positive as well as a negative regulator of functional differentiation depending on the cell type and the genes studied. It also acts in a hierarchical fashion, exacting higher and higher degrees of stringency to achieve full functional differentiation. Regulation by ECM is closely interrelated with the action of other regulators of cellular function, such as growth factors and hormones. But ECM may exert its regulation of gene expression by mechanisms distinct from those known for soluble transcription factors. In this short review, we describe three systems in which ECM has been shown to play a crucial role in functional differentiation, but we emphasize mainly the work from our own laboratory to provide a more in-depth analysis of one system. The three systems are: mouse mammary epithelial cells, rat hepatocytes, and human keratinocytes. The crucial role of ECM in normal cell differentiation implies that its alteration may have serious consequences in malignancies and other diseases. The current functional cell culture models could provide powerful tools not only for understanding regulation of normal cell function but also for the studies of tumorigenesis and possibly cancer therapy.

Expression patterns of laminin receptor splice variants α6Aβ1 and α6Bβ1 suggest different roles in mouse development

“…Moreover, the fact that a6 expression is completely downregulated in the myocardium late (day 16) in embryogenesis (Buck et al, 19931, shows the existence of a timewindow for a6A function in myocardial development, which suggests a role for the a6Apl integrin in a timed developmental event, such as the differentiation of cardiac muscle. It is well known that laminin is important in the differentiation of a variety of cell types, such as mammary gland epithelial cells, keratinocytes, hepatocytes, kidney epithelial cells, and skeletal muscle myoblasts (reviewed in Adams and Watt, 1993;Lin and Bissell, 1993), and our data are compatible with an analogous role for laminin and the a6AP1 integrin in the developing heart. Very little is known about how cardiac myogenesis is controlled, but it is clear that the transcription factors involved are not the same as those controlling the development of skeletal muscle (Buckingham, 1994).…”

The microenvironmental determinants for kidney epithelial cyst morphogenesis

“…The signaling involved in MDCK cyst formation has emerged from various studies (Mangoo-Karim et al, 1989;Orellana and Marfella-Scivittaro, 2000;O'Brien et al, 2001;Schramek et al, 2003;Yu et al, 2005). The importance of the microenvironment in cystogenesis is well documented (Lin and Bissell, 1993;Kleinman et al, 2003). The environmental determinants for MDCK cystogenesis, however, have not been systematically assessed (Wang et al, 1990a(Wang et al, , 1994.…”

“…Cell-ECM interaction, cell-cell interaction, and soluble factor stimulation are considered to be three major extrinsic factors essential for cystogenesis (Grobstein, 1956;Saxen and Sariola, 1987;Laurie et al, 1989;Wang et al, 1990a, b). Among these extrinsic factors, the ECM plays a key role in the differentiation and morphogenesis of epithelia (Emerman and Pitelka, 1977;Emerman et al, 1979;Parry et al, 1987;Lin and Bissell, 1993). For example, attachment of epithelial cells to the ECM is required for the establishment of cellular polarity and subsequent morphogenesis (Nelson, 1992;Rodriguez-Boulan and Powell, 1992).…”

Improved growth factor directed vascularization into fibrin constructs through inclusion of additional extracellular molecules

“…Collagen is known to produce proliferative and functional responses through cell binding and signaling (Lin and Bissell, 1993;Weinberg and Bell, 1985). Collagen and collagen-derived peptides have also been shown to be chemoattractants for fibroblasts in vitro (Postlethwaite et al, 1978).…”