Abstract
The mechanisms underlying early islet graft failure are not entirely clear, but are thought to involve ischemic injury due to delayed vascularization. We hypothesize that blood vessels play an active role in cell-cell communications supporting islet survival and engraftment. To test this hypothesis and to uncouple endothelial cell (EC)-generated signaling stimuli from their nutritional and gas exchange functions, we developed three dimensional (3D) endothelial vessel networks in engineered pancreatic tissues prepared from islets, fibroblasts and ECs. The tri-culture setup, seeded on highly porous biocompatible polymeric scaffolds closely mimics the natural anatomical context of pancreatic vasculature. Enhanced islet survival correlating with formation of functional tube-like endothelial vessels was demonstrated. Addition of foreskin fibroblasts to islet-endothelial cultures promoted tube-like structure formation, which further supported islet survival as well as insulin secretion. Gene expression profiles of EC growth factors, extracellular matrix (ECM), morphogenes and differentiation markers were significantly different in 2D versus 3D culture systems and were further modified upon addition of fibroblasts. Implantation of prevascularized islets into diabetic mice promoted survival, integration and function of the engrafted engineered tissue, supporting the suggested role of ECs in islet survival. These findings present potential strategies for preparation of transplantable islets with increased survival prospects.
Highlights
Islet transplantations have been attracting increasing attention in recent years, as they carry new hope for successful restoration of glycemic control in Type 1 diabetes patients [1]
Double von Willebrand factor (vWF) and insulin cross-section labeling confirmed the central role of 3D lumen-forming endothelial cell (EC) in morphological preservation and survival of islets, grown in the absence of blood flow
Islets tri-cultured with ECs and human foreskin fibroblast (HFF) on 3D scaffolds remained intact and expressed insulin even after 28 days in culture; 80% were still viable by the end of the experiment (Fig. 2a–c)
Summary
Islet transplantations have been attracting increasing attention in recent years, as they carry new hope for successful restoration of glycemic control in Type 1 diabetes patients [1]. Only moderate success has been achieved due to donor organ shortage and low islet allograft survival rates, increasing the number of islets required per procedure. One of the most likely reasons for the poor success rates relates to the avascular nature of islets grafts, following their collagenase-based purification and free transplantation [2,3]. We hypothesize that the non-nutritional EC-stimulated signals may be paramount to in vitro culturing of islets for the purpose of boosting early graft infusion survival prospects. In this manner, ECs may be critical to enhancing success rates of islet-based therapy
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