Islet transplantation is associated with a high rate of early graft failure caused by early immune attack and poor functionality of islets. Apoptosis of islet cells appears soon after islet isolation and primarily involves the ␤-cell. The purpose of this study was to determine the effect of ligation to extracellular matrix (ECM) proteins on survival of the islets of Langerhans following islet isolation. Islets that had been cultured for 24 h on collagen type I showed an islet survival of 59.7 ؎ 8.7%, while islets that had been cultured on collagen type IV and laminin showed an islet survival of 88.6 ؎ 10.3 and 94.3 ؎ 5.6%, respectively. Islets that had been pretreated with anti-␤1 antibodies and argenin-glycin-aspartic acid (RGD) peptides showed a decrease in the level of apoptosis by a factor of 2.5 and 3.1, respectively, and an increase of phospho-Akt Ser 473 activity by a factor of 3.1 and 2.9, respectively, compared with untreated islets. When detached from their natural ECM surrounding in the pancreas, islet cells undergo apoptosis, unless islets are cultured on collagen IV or laminin or treated with anti-␤1 integrin antibodies or RGD peptides to mimic ECM ligation. These results indicate that inhibition of anoikis may offer opportunities to improve function and viability of islet cells. Diabetes 55:312-317, 2006 T ransplantation of islets of Langerhans has the potential to become a widely applicable treatment for type 1 diabetes. Unfortunately, islet transplantation is associated with a high rate of early graft failure (1-4), which is caused by early immune attack, poorly functioning islets that were presumably damaged during isolation, or both. Apoptosis of islet cells appears soon after islet isolation and primarily involves the ␤-cell (5).During islet isolation by collagenase treatment, during purification, and during pretransplanting culture, the microenvironment of the islet is destroyed. Extracellular matrix (ECM) is an important component of the islet microenvironment that prevents cellular stress, which could impair ␤-cell function and survival (6,7). The islet basement membrane is composed of the ECM proteins laminin, fibronectin, and collagen types I, III, IV, and V (8,9). Cell-matrix interactions are necessary because they provide signals for proliferation, differentation, and migration (10). These interactions are mediated by integrins, which are a diverse class of ␣␤ heterodimeric transmembrane receptors that form ligands for the ECM (10 -12).Cells disconnected from their ECM can undergo apoptosis by an integrin-mediated death signal called anoikis (6,13,14). The pancreatic cells express the integrins ␣3␤1, ␣5␤1, and ␣v␤3 (7,15), which are also known to bind argenin-glycin-aspartic acid (RGD) sequences on ECM molecules. Cell attachment mediated by the ␣5␤1 and the ␣v␤3 integrin promotes cell survival by upregulation of Bcl-2 (16,17). Integrins are believed to mediate survival by activating a specific signaling pathway. One of its ligands is integrin-linked kinase (ILK), which can phosphorylate...

No abstract