Extracellular matrix molecules and their potential contribution to the function of transplanted pancreatic islets

Abstract

Extracellular matrix (ECM) molecules are responsible for structural and biochemical support, as well as for regulation of molecular signalling and tissue repair in many organ structures, including the pancreas. In pancreatic islets, collagen type IV and VI, and laminins are the most abundant molecules, but other ECM molecules are also present. The ECM interacts with specific combinations of integrin α/β heterodimers on islet cells and guides many cellular processes. More specifically, some ECM molecules are involved in beta cell survival, function and insulin production, while others can fine tune the susceptibility of islet cells to cytokines. Further, some ECM induce release of growth factors to facilitate tissue repair. During enzymatic isolation of islets for transplantation, the ECM is damaged, impacting islet function. However, restoration of the ECM in human islets (for example by adding ECM to the interior of immunoprotective capsules) has been shown to enhance islet function. Here, we provide current insight into the role of ECM molecules in islet function and discuss the clinical potential of ECM manipulation to enhance pancreatic islet function and survival.

Keywords: Collagen; Cytokines; Extracellular matrix; Graft; Islet; Laminin; Review.

Fig. 1

Cell function and survival is determined by ECM–cell interactions. (a) All cells require interaction with ECM for homeostasis of cellular functions. (b) Loss of ECM–cell interactions owing to mechanical forces or enzymatic digestion trigger cell-death processes, such as apoptosis. This figure is available as part of a downloadable slideset

Fig. 2

Summary of the current knowledge on ECM–cell interactions within islets. Integrin receptors bind to and interact with several ECM molecules in the pancreas, including collagen, RGD, fibronectin and laminin. Integrins, Src family kinases, and Rho GTPases are essential in mediating cellular responses downstream of ECM engagement. Stimulation of integrins initiate signalling cascades that ultimately affect the expression of genes influencing survival, growth and differentiation of cells. For example, FAK activation and subsequent activation of Akt and MAPKs can result from ECM–integrin interactions in the pancreas, whilst other integrin subunits crosstalk with growth factor receptors like EGFR. This figure is available as part of a downloadable slideset

Fig. 3

Supplementation of ECM in capsules for immuno-isolation of pancreatic islets enhance functional survival of the graft. (a) Specific ECM molecules may be added to islets before transplantation to enhance the functional survival of islets. For example, collagen IV and laminin sequences, such as RGD, LRE and PDSGR, have positive effects on the function of isolated human islets. (b) Supplemented ECM can mimic/interact with various molecules on the islet cell membrane. Immuno-isolation of islets by encapsulation has been used to demonstrate that ECM supplementation can promote islet cell survival. Encapsulation of islets in an immunoprotective but semipermeable membrane allows for successful transplantation of islets without the need for immunosuppression. This figure is available as part of a downloadable slideset