Engineered vascular beds provide key signals to pancreatic hormone-producing cells.
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.
Department of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel.
Keren
K
Kaufman-Francis
Jacob
J
Koffler
Noa
N
Weinberg
Yuval
Y
Dor
Shulamit
S
Levenberg
D000818:Animals; D001808:Blood Vessels / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000098:blood supply; D016381:Islets of Langerhans Transplantation; D051379:Mice; D009024:Morphogenesis / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics; D019919:Prosthesis Implantation; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D023822:Tissue Engineering / Q000379:methods*; D014022:Tissue Survival; D015854:Up-Regulation / Q000235:genetics
D007328:Insulin