Fibronectin inhibits the terminal differentiation of human keratinocytes

Abstract

In the epidermis proliferation of keratinocytes is restricted to the basal layer, which is in contact with the basement membrane, and cells undergo terminal differentiation as they move upwards through the suprabasal layers. In stratified cultures of human keratinocytes, upward migration is a consequence, not a cause, of terminal differentiation and occurs because keratinocytes become less adhesive to their substratum and to one another. Most keratinocytes can be induced to differentiate to completion by placing them in suspension in methylcellulose: within 12 h DNA synthesis is irreversibly inhibited and by 24 h most cells express involucrin (ref 4; P. A. Hall, J.C.A. and F.M.W., unpublished observations). Here we report that when fibronectin is added to the methylcellulose, keratinocytes still withdraw from the cell cycle, but induction of involucrin expression is largely inhibited. The effect of fibronectin is concentration- and time-dependent and is mediated by a receptor of the integrin family. These results provide an explanation for why overt terminal differentiation is normally restricted to suprabasal cells, whereas cell-cycle withdrawal occurs within the basal layer; they also have important implications for the mechanism of epidermal wound healing. Furthermore, our data show that the binding of an extracellular matrix protein to its receptor can regulate differentiated gene expression in the absence of changes in cell shape.

Optimised retroviral infection of human epidermal keratinocytes: long-term expression of transduced integrin gene following grafting on to SCID mice

“…Since the average transit time from the basal to the cornified layers is about 1 month in normal human epidermis we are reasonably confident that the stem cells were targeted in the original infection. Although the YPRF mutant used in the grafts did not affect keratinocyte proliferation in culture or mediate ECM adhesion 18 (data not shown) we have evidence that it can suppress suspension-induced terminal differentiation 15,16 (data not shown) and thus we cannot rule out the possibility that expression of the YPRF mutant confers a selective advantage on the transduced cells. It will now be interesting to test other transduced genes in the experimental model.…”

“…For the experiments to be reported the chick ␤ 1 integrin subunit was chosen as the transduced gene because expression and function could be monitored on a cell-bycell basis and because of the role of ␤ 1 integrins in regulating keratinocyte terminal differentiation. 15,16 …”

2-acetylaminofluorene dose-dependent differentiation of rat oval cells into hepatocytes: Confocal and electron microscopic studies

“…24 In the skin, however, the loss of contact is a stimulus for differentiation for the keratinocytes. 25 The hepatocytes have no contact with laminin containing structured basement membrane. Yin et al 26 reported that isolated hepatic stem cells expressed biliary or hepatocytic phenotypes in culture, depending on the presence or absence of basement membrane matrix (Matrigel).…”

Integrins in regulation of tissue development and function

“…Integrin-mediated adhesion also primes monocytes for inflammatory responses [51]. Finally, the expression of involucrin, which is associated with terminal differentiation of cultured keratinocytes under semisolid conditions, is inhibited by the integrin-ligand fibronectin [52].…”