Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell & Tissue Engineering, Medicine, Research & Experimental, Transplantation, Cell Biology, Research & Experimental Medicine, Human pancreatic duct cell, Islet transplantation, Immunosuppressant, Cytoldnes, Angiogenesis, Dedifferentiation, ENDOTHELIAL GROWTH-FACTOR, HUMAN ISLET PREPARATIONS, BETA-CELLS, MYCOPHENOLATE-MOFETIL, DIABETES-MELLITUS, EDMONTON PROTOCOL, TRANSPLANTATION, RAPAMYCIN, RAT, GRAFT, Adolescent, Adult, Animals, Apoptosis, Cell Proliferation, Cellular Reprogramming, Chemokines, Chick Embryo, Chickens, Child, Chorioallantoic Membrane, Cytokines, Female, Humans, Immunosuppressive Agents, Interleukin-8, Male, Mice, Mice, Inbred NOD, Mice, SCID, Middle Aged, Neovascularization, Physiologic, Pancreatic Ducts, Sirolimus, Tacrolimus, Vascular Endothelial Growth Factor A, Young Adult, 06 Biological Sciences, 10 Technology, 11 Medical and Health Sciences, Neurology & Neurosurgery, 31 Biological sciences

Abstract:

The presence of pancreatic duct cells in clinical islet grafts may affect long-term metabolic success. Human pancreatic duct cells express factors that may exert both protective and damaging effects on islet cells in the graft. Here, we studied the potential of commonly used immunosuppressive drugs in islet transplantation - sirolimus, tacrolimus and mycophenolate mofetil (MMF) - to influence the inflammatory and angiogenic capacity of human pancreatic duct cells in addition to their proliferation and reprogramming abilities. Our data show that the expression of specific pro-inflammatory cytokines by the human pancreatic duct cells was either unaltered or inhibited by the immunosuppressants studied, especially tacrolimus and MMF, whereas expression of chemotactic and angiogenic factors was unaffected. Although none of the immunosuppressants directly led to duct cell death, MMF prevented duct cell proliferation and sirolimus inhibited Ngn-3-mediated duct-to-(neuro)endocrine cell reprogramming. Our data indicate that the immunosuppressant tacrolimus was the least aggressive on the angiogenic, proliferative, and reprogramming potential of human pancreatic duct cells, while it was most powerful in inhibiting inflammatory cytokines, which may influence the outcome of islet transplantation.