Cadherin Engagement Protects Human β-Cells from Apoptosis

The aim of this study was to assess the expression of different types of cadherins in human islets and their role in human beta-cell apoptosis. Expression of E-, N-, and P-cadherins was studied by immunofluorescence on pancreas sections and islet cells, and by Western blotting on protein extracts of isolated islets and islet cells. The effects of specific cadherins on cell adhesion and apoptosis were studied using chimeric proteins containing functional E-, N-, or P-cadherin ectodomains fused to Fc fragment of Ig (E-cad/Fc, N-cad/Fc, and P-cad/Fc) and immobilized on glass substrate. beta-Cells were identified by immunofluorescence for insulin and apoptotic cells by terminal deoxynucleotide transferase-mediated 2'-deoxyuridine, 5'-triphosphate nick-end labeling. By immunofluorescence, we showed that E-and N-, and not P-, cadherins were expressed at the surface of islet cells. By triple staining, we showed that E-cadherin was expressed at similar extent in beta- and alpha-cells, whereas N-cadherin was preferentially expressed in beta-cells. These results were confirmed by Western blot analysis using protein extracts from fluorescence-activated cell sorting-sorted beta- and non-beta-cells. Adhesion tests showed that the affinity of islet cells for E-cad/Fc and N-cad/Fc and not for P-cad/Fc was increased compared with control. By terminal deoxynucleotide transferase-mediated 2'-deoxyuridine, 5'-triphosphate nick-end labeling, we showed that the percentage of apoptotic cells was lower in aggregated beta-cells compared with single beta-cells and that attachment to E-cad/Fc and N-cad/Fc and not to P-cad/Fc decreased apoptosis of single beta-cells compared with control. Our results show that at least E- and N-cadherins are expressed at the surface of human beta-cells and that these adhesion molecules are involved in the maintenance of beta-cell viability. (Endocrinology 152: 4601-4609, 2011)