Modification of Human Islet Preparation: An Effective Approach to Improve Graft Outcome After Islet Transplantation?

Abstract

Revascularisation of transplanted islets is an essential prerequisite for graft survival and function. However, current islet isolation procedures deprive the islets of endothelial tubulets. This may have a detrimental effect on the revascularisation process of islets following transplantation. We hypothesise that modification of the isolation procedure that preserves islet endothelial vessels may improve the islet revascularisation process following transplantation. Here, we present a modified islet isolation method by which a substantial amount of endothelial cells still attached to the islets could be preserved. The islets with preserved endothelial cells isolated by this method were revascularised within 3 days, not observed in islets isolated by standard methods. Further, we observed that grafts of islets isolated by standard methods had more patches of dead tissue than islet grafts obtained by the modified method, indicating that attached endothelial cells may play an important role in the islet revascularisation process and potentially help to improve the transplantation outcome.

Key words

human islet - transplantation - endothelium cells - revascularisation

• References

• 1 Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343: 230-238
• 2 Ludwig B, Reichel A, Kruppa A, Ludwig S, Steffen A, Weitz J, Bornstein SR. Islet transplantation at the Dresden Diabetes Center: five years’ experience. Horm Metab Res 2014; 47: 4-8
• 3 Byrne ML, Hopkins D, Littlejohn W, Beckford R, Srinivasan P, Heaton N, Amiel SA, Choudhary P. Outcomes for adults with type 1 diabetes referred with severe hypoglycaemia and/or referred for islet transplantation to a specialist hypoglycaemia service. Horm Metab Res 2014; 47: 9-15
• 4 Shapiro AM. State of the art of clinical islet transplantation and novel protocols of immunosuppression. Curr Diab Rep 2011; 11: 345-354
• 5 Canadian Diabetes Association Clinical Practice Guidelines Expert Committee . Pancreas and Islet Transplantation. Can J Diabetes 2013; 37: S94-S96
• 6 Ludwig B, Reichel A, Steffen A, Zimerman B, Schally AV, Block NL, Colton CK, Ludwig S, Kersting S, Bonifacio E, Solimena M, Gendler Z, Rotem A, Barkai U, Bornstein SR. Transplantation of human islets without immunosuppression. Proc Natl Acad Sci USA 2013; 110: 19054-19058
• 7 Tomei AA, Manzoli V, Fraker CA, Giraldo J, Velluto D, Najjar M, Pileggi A, Molano RD, Ricordi C, Stabler CL, Hubbell JA. Device design and materials optimization of conformal coating for islets of Langerhans. Proc Natl Acad Sci USA 2014; 111: 10514-10519
• 8 Giuliani M, Moritz W, Bodmer E, Dindo D, Kugelmeier P, Lehmann R, Gassmann M, Groscurth P, Weber M. Central necrosis in isolated hypoxic human pancreatic islets: evidence for postisolation ischemia. Cell Transplant 2005; 14: 67-76
• 9 Van Deijnen JH, Van Suylichem PT, Wolters GH, Van Schilfgaarde R. Distribution of collagens type I, type III and type V in the pancreas of rat, dog, pig and man. Cell Tissue Res 1994; 277: 115-121
• 10 Hughes SJ, Clark A, McShane P, Contractor HH, Gray DW, Johnson PR. Characterisation of collagen VI within the islet-exocrine interface of the human pancreas: implications for clinical islet isolation?. Transplantation 2006; 81: 423-426
• 11 Konstantinova I, Lammert E. Microvascular development: learning from pancreatic islets. Bioessays 2004; 26: 1069-1075
• 12 Johansson M, Andersson A, Carlsson PO, Jansson L. Perinatal development of the pancreatic islet microvasculature in rats. J Anat 2006; 208: 191-196
• 13 Eberhard D, Kragl M, Lammert E. ‘Giving and taking’: endothelial and beta-cells in the islets of Langerhans. Trends Endocrinol Metab 2010; 21: 457-463
• 14 Cleaver O, Melton DA. Endothelial signaling during development. Nat Med 2003; 9: 661-668
• 15 Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci USA 2006; 103: 2334-2339
• 16 Olsson R, Carlsson PO. The pancreatic islet endothelial cell: emerging roles in islet function and disease. Int J Biochem Cell Biol 2006; 38: 710-714
• 17 Nyman LR, Wells KS, Head WS, McCaughey M, Ford E, Brissova M, Piston DW, Powers AC. Real-time multidimensional in vivo imaging used to investigate blood flow in mouse pancreatic islets. J Clin Invest 2008; 118: 3790-3797
• 18 Olsson R, Carlsson PO. Better vascular engraftment and function in pancreatic islets transplanted without prior culture. Diabetologia 2005; 48: 469-476
• 19 Nyqvist D, Speier S, Rodriguez-Diaz R, Molano RD, Lipovsek S, Rupnik M, Dicker A, Ilegems E, Zahr-Akrawi E, Molina J, Lopez-Cabeza M, Villate S, Abdulreda MH, Ricordi C, Caicedo A, Pileggi A, Berggren PO. Donor islet endothelial cells in pancreatic islet revascularization. Diabetes 2011; 60: 2571-2577
• 20 Wolters GH, Vos-Scheperkeuter GH, van Deijnen JH, van Schilfgaarde R. An analysis of the role of collagenase and protease in the enzymatic dissociation of the rat pancreas for islet isolation. Diabetologia 1992; 35: 735-742
• 21 Saito Y, Goto M, Maya K, Ogawa N, Fujimori K, Kurokawa Y, Satomi S. The influence of brain death on tissue factor expression in the pancreatic tissues and isolated islets in rats. Transplant Proc 2009; 41: 307-310
• 22 Koh A, Senior P, Salam A, Kin T, Imes S, Dinyari P, Malcolm A, Toso C, Nilsson B, Korsgren O, Shapiro AM. Insulin-heparin infusions peritransplant substantially improve single-donor clinical islet transplant success. Transplantation 2010; 89: 465-471
• 23 Nilsson B, Ekdahl KN, Korsgren O. Control of instant blood-mediated inflammatory reaction to improve islets of Langerhans engraftment. Curr Opin Organ Transplant 2011; 16: 620-626
• 24 Naziruddin B, Iwahashi S, Kanak MA, Takita M, Itoh T, Levy MF. Evidence for instant blood-mediated inflammatory reaction in clinical autologous islet transplantation. Am J Transplant 2014; 14: 428-437
• 25 van der Windt DJ, Echeverri GJ, Ijzermans JN, Cooper DK. The choice of anatomical site for islet transplantation. Cell Transplant 2008; 17: 1005-1014
• 26 Cantarelli E, Melzi R, Mercalli A, Sordi V, Ferrari G, Lederer CW, Mrak E, Rubinacci A, Ponzoni M, Sitia G, Guidotti LG, Bonifacio E, Piemonti L. Bone marrow as an alternative site for islet transplantation. Blood 2009; 114: 4566-4574
• 27 Olsson R, Maxhuni A, Carlsson PO. Revascularization of transplanted pancreatic islets following culture with stimulators of angiogenesis. Transplantation 2006; 82: 340-347
• 28 Johansson U, Rasmusson I, Niclou SP, Forslund N, Gustavsson L, Nilsson B, Korsgren O, Magnusson PU. Formation of composite endothelial cell-mesenchymal stem cell islets: a novel approach to promote islet revascularization. Diabetes 2008; 57: 2393-2401
• 29 Brady AC, Martino MM, Pedraza E, Sukert S, Pileggi A, Ricordi C, Hubbell JA, Stabler CL. Proangiogenic hydrogels within macroporous scaffolds enhance islet engraftment in an extrahepatic site. Tissue Eng Part A 2013; 19: 2544-2552
• 30 Huang GC, Zhao M, Jones P, Persaud S, Ramracheya R, Löbner K, Christie MR, Banga JP, Peakman M, Sirinivsan P, Rela M, Heaton N, Amiel S. The development of new density gradient media for purifying human islets and islet quality assessments. Transplantation 2004; 77: 143-145
• 31 Zhao M, Amiel SA, Christie MR, Rela M, Heaton N, Huang GC. Insulin-producing Cells Derived from Human Pancreatic Non-endocrine Cell Cultures Reverse Streptozotocin-induced Hyperglycaemia in Mice. Diabetologia 2005; 48: 2051-2061
• 32 Zhao M, Muiesan P, Amiel SA, Srinivasan P, Asare-Anane H, Fairbanks L, Persaud S, Jones P, Jones J, Ashraf S, Littlejohn W, Rela M, Heaton N, Huang GC. Human islets derived from donors after cardiac death are fully biofunctional. Am J Transpl 2007; 7: 2318-2325
• 33 Zhao M, Amiel SA, Christie MR, Muiesan P, Srinivasan P, Littlejohn W, Rela M, Arno M, Heaton N, Huang GC. Evidence for the presence of stem cell-like progenitor cells in human adult pancreas. J Endocrinol 2007; 195: 407-414
• 34 Zhao M, Amiel SA, Ajami S, Jiang J, Rela M, Heaton N, Huang GC. Amelioration of Streptozotocin-induced Diabetes in Mice with Cells Derived from Human Marrow Stromal Cells. PLoS ONE 3: e2666
• 35 Brunicardi FC, Stagner J, Bonner-Weir S, Wayland H, Kleinman R, Livingston E, Guth P, Menger M, McCuskey R, Intaglietta M, Charles A, Ashley S, Cheung A, Ipp E, Gilman S, Howard T, Passaro Jr E. Microcirculation of the islets of Langerhans. Long Beach Veterans Administration Regional Medical Education Center Symposium. Diabetes 1996; 45: 385-392
• 36 Olsson R, Carlsson PO. The pancreatic islet endothelial cell: emerging roles in islet function and disease. Int J Biochem Cell Biol 2006; 38: 710-714
• 37 Ludwig B, Zimerman B, Steffen A, Yavriants K, Azarov D, Reichel A, Vardi P, German T, Shabtay N, Rotem A, Evron Y, Neufeld T, Mimon S, Ludwig S, Brendel MD, Bornstein SR, Barkai U. A novel device for islet transplantation providing immune protection and oxygen supply. Horm Metab Res 2010; 42: 918-922
• 38 Oh BJ, Oh SH, Jin SM, Suh S, Bae JC, Park CG, Lee MS, Lee MK, Kim JH, Kim KW. Co-transplantation of bone marrow-derived endothelial progenitor cells improves revascularization and organization in islet grafts. Am J Transplant 2013; 13: 1429-1440