Impact of integrin-matrix interaction and signaling on insulin gene expression and the mesenchymal transition of human beta-cells.

A critical shortage of donor pancreata currently prevents the development of a universal cell-based therapy for type I diabetes. The ex vivo expansion of insulin-producing beta-cells offers a potential solution but is problematic due to the inherent tendency of these cells to transition into mesenchymal-like cells that are devoid of function. Here, we demonstrate for the first time that exposure to elements of the extracellular matrix (ECM) directly potentiates the mesenchymal transition of cultured fetal beta-cells and causes associated declines in insulin gene expression. Individual ECM constituents varied in their ability to induce such responses, with collagen-IV (C-IV) and fibronectin inducing strong responses, whereas laminin-1 had no significant effect. Mesenchymal transition and concomitant losses in insulin gene expression observed on C-IV were found to be dependent on beta(1)-integrin ligation and were augmented in the presence of hepatocyte growth factor. Importantly, selective inhibition of c-Src, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) prior to exposure to C-IV prevented mesenchymal transition and effectively preserved insulin expression. Fetal beta-cells undergoing mesenchymal transition were found to acquire alpha(1)beta(1) expression, and ligation of this integrin then promotes declines in insulin gene expression and a marked increase in beta-cell motility. Inhibition of Src-, ERK-, or JNK-dependent signaling combined with the selective regulation of matrix exposure may ultimately facilitate the development of more effective beta-cell expansion protocols. (c) 2010 Wiley-Liss, Inc.