β1 integrin–extracellular matrix interactions are essential for maintaining exocrine pancreas architecture and function

Abstract

Integrin receptors are responsible for integrating extracellular matrix signals inside the cell. The most prominent integrin receptor, b1 integrin, has a role in cell function, survival and differentiation. Recently, we demonstrated a profound in vivo role of b1 integrin expression in the pancreas on glucose homeostasis and islet function. Here, we extend these results by examining the role of b1 integrin in exocrine pancreatic structure and function. Adult C57Bl/6 mice hemizygous for a collagen type Ia2 (Col1a2) promoter-controlled tamoxifen-inducible Cre recombinase gene and homozygous for loxP-b1 integrin were injected with tamoxifen or corn oil to generate mice deleted or not for b1 integrin. Pancreata derived from these male mice were analyzed by quantitative reverse transcriptase-polymerase chain reaction, western blot and immunofluorescence. Our results showed that b1 integrin-deficient mice displayed a significant decrease in pancreas weight with a significant reduction of amylase, regenerating islet-derived protein II and carboxypeptidase-A expression (Po0.05-0.01). Compared with control pancreata, b1 integrin-deficient pancreata showed reduced mRNA expression of extracellular matrix (collagen type Ia2, fibronectin and laminin) genes (Po0.05), detached acini clusters and lost focal adhesion structure. Moreover, b1 integrin-deficient pancreatic acinar cells displayed decreased proliferation (Po0.05) and increased apoptosis (Po0.001). Apoptosis was reduced to that of controls when isolated exocrine clusters were cultured in media supplemented with extracellular matrix proteins. Taken together, these results implicate b1 integrin as an essential component for maintaining exocrine pancreatic structure and function. Integrin receptors have a significant role in cell-cell and cellextracellular matrix (ECM) contacts in many different tissue types. There are 18 a and 8 b receptors capable of forming 24 heterodimeric interactions; yet, half these interactions are made up by b1 integrin receptors. 1 This b1 integrin receptor group is largely responsible for attachment to the ECM. 2 Upon stimulation, b1 integrin has been shown to mediate cell motility, survival, proliferation and differentiation. [2][3][4][5] Pancreatic acini are enclosed round structures that produce digestive enzymes. 6 Basal lamina covers the acini at the basal surface, stimulating acini integrin receptors. 6 Pancreatic stellate cells (PSCs) are identified as periacinar fibroblast-like cells of the pancreas that express glial fibrillary acidic protein (GFAP) and produce ECM proteins in support of surrounding tissue. 7 PSCs are also, in part, responsible for the fibrosis observed in chronic pancreatitis. 8,9 Previous studies have shown that a3b1 integrin is essential for proper apical/ basolateral cell surface receptor organization and basement membrane formation in the submandibular gland. 10 As well, b1 integrin deficiency has shown to interfere with laminin-1 expression and basement membrane synthesis and assembly in embryoid bodies 11 and te...

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