Laminin and collagen IV inclusion in immunoisolating microcapsules reduces cytokine-mediated cell death in human pancreatic islets

Extracellular matrix (ECM) molecules have several functions in pancreatic islets including provision of mechanical support and prevention of cytotoxicity during inflammation. During islet isolation, ECM-connections are damaged and are not restored after encapsulation and transplantation. Inclusion of specific combinations of collagen type IV and laminins in immunoisolating capsules can enhance survival of pancreatic islets. Here we investigated whether ECM can also enhance survival and lower susceptibility of human islets to cytokine-mediated cytotoxicity. To this end, human islets were encapsulated in alginate with collagen IV and either RGD, LRE, or PDSGR, i.e. laminin sequences. Islets in capsules without ECM served as control. The encapsulated islets were exposed to IL-1β, IFN-γ, and TNF-α for 24 and 72 hours. All combinations of ECM improved the islet-cell survival and reduced necrosis and apoptosis after cytokine exposure (p<0.01). Collagen IV-RGD and collagen IV-LRE reduced danger-associated molecular patterns (DAMPs) release from islets (p<0.05). Moreover, collagen IV-RGD and collagen IV-PDGRS but not collagen IV-LRE reduced NO release from encapsulated human islets (p<0.05). This reduction correlated with a higher oxygen consumption rate of islets in capsules containing collagen IV-RGD and collagen IV-PDGRS. Islets in capsules with collagen IV-LRE showed more dysfunction and OCR was not different from islets in control capsules without ECM. Our study demonstrates that incorporation of specific ECM molecules such as collagen type IV with the laminin sequences RGD and PDSGR in immunoisolated islets can protect against cytokine toxicity. This article is protected by copyright. All rights reserved.