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

• Published in: Journal of cellular physiology 2010-07, Vol.224 (1), p.101-111
• Main Authors: Kaido, Thomas J., Yebra, Mayra, Kaneto, Hideaki, Cirulli, Vincenzo, Hayek, Alberto, Montgomery, Anthony M.P.
• Format: Article
• Language: English
• Subjects: Aged; Beta cells; Cell Adhesion; Cell Movement; Cell Transdifferentiation - drug effects; Cells, Cultured; Collagen Type IV - metabolism; Diabetes mellitus; Down-Regulation; Enzyme Activation; Exposure; Extracellular matrix; Extracellular Matrix Proteins - metabolism; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Fetuses; Fibronectin; Fibronectins - metabolism; Gene expression; Gestational Age; Growth factors; Hepatocyte growth factor; Hepatocyte Growth Factor - metabolism; Humans; Insulin; Insulin - genetics; Insulin - metabolism; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Integrin alpha1beta1 - metabolism; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; JNK protein; Kinases; Laminin; Laminin - metabolism; Mesoderm - metabolism; Middle Aged; Pancreas - embryology; Pancreas - metabolism; Phenotype; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; src-Family Kinases; Transfection; Vimentin - metabolism
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.22101

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 β‐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 β‐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 β1‐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 β‐cells undergoing mesenchymal transition were found to acquire α1β1 expression, and ligation of this integrin then promotes declines in insulin gene expression and a marked increase in β‐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 β‐cell expansion protocols. J. Cell. Physiol. 224:101–111, 2010 © 2010 Wiley‐Liss, Inc.