Current Concepts of Using Pigs as a Source for Beta-Cell Replacement Therapy of Type 1 Diabetes

Current Molecular Biology Reports - Tập 2 - Trang 73-82 - 2016
Bruno Reichart1, Jochen Seissler2, Barbara Ludwig3,4, Eckhard Wolf3,5,6, Nikolai Klymiuk5,6
1Walter Brendel Center of Experimental Medicine, LMU Munich, Munich, Germany
2Diabetes Center, Medizinische Klinik und Poliklinik IV, LMU Munich, Munich, Germany
3Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU Dresden and DZD-German Centre for Diabetes Research, Neuherberg, Germany
4Department of Medicine III, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany
5Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany
6Center for Innovative Medical Models (CiMM), LMU Munich, Oberschleißheim, Germany

Tóm tắt

The global prevalence of insulin-dependent diabetes mellitus is rapidly increasing. In spite of major improvements in insulin treatment regimens and diabetes technology (e.g., artificial pancreas devices), glucose control remains problematic in a substantial proportion of diabetic patients. Those patients may benefit from beta-cell replacement therapies. Allotransplantation of pancreas or isolated pancreatic islets is limited by the small number of organ donors. Thus, alternative sources of beta-cells are being developed and tested. These include endocrine progenitor cells or mature beta-cells derived from pluripotent human stem cells and attempts to derive human pancreas tissue in animal hosts by interspecific chimeric complementation experiments. Xenotransplantation of porcine islets is a realistic alternative option. Immune rejection of xenoislets can be prevented by immunosuppression of the recipient or by encapsulation of the islets in microdevices or macrodevices. Using precise and efficient genetic engineering of donor pigs, immune-protected xenoislets with improved functionality can be generated.

Tài liệu tham khảo

Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383:69–82. Diaz-Valencia PA, Bougneres P, Valleron AJ. Global epidemiology of type 1 diabetes in young adults and adults: a systematic review. BMC Public Health. 2015;15:255. American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In standards of medical care in diabetes - 2015. Diabetes Care. 2015;38 Suppl 1:S41–8. Yeh HC, Brown TT, Maruthur N, et al. Comparative effectiveness and safety of methods of insulin delivery and glucose monitoring for diabetes mellitus: a systematic review and meta-analysis. Ann Intern Med. 2012;157:336–47. Farrington C. The artificial pancreas: challenges and opportunities. Lancet Diabetes Endocrinol. 2015;3:937. Choudhary P, Rickels MR, Senior PA, et al. Evidence-informed clinical practice recommendations for treatment of type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care. 2015;38:1016–29. Forlenza GP, Buckingham B, Maahs DM. Progress in diabetes technology: developments in insulin pumps, continuous glucose monitors, and progress towards the artificial pancreas. J Pediatr. 2016;169:13–20. Reichart B, Niemann H, Chavakis T, et al. Xenotransplantation of porcine islet cells as a potential option for the treatment of type 1 diabetes in the future. Horm Metab Res. 2015;47:31–5. Niclauss N, Morel P, Berney T. Has the gap between pancreas and islet transplantation closed? Transplantation. 2014;98:593–9. Ludwig B, Ludwig S, Steffen A, Saeger HD, Bornstein SR. Islet versus pancreas transplantation in type 1 diabetes: competitive or complementary? Curr Diab Rep. 2010;10:506–11. Barton FB, Rickels MR, Alejandro R, et al. Improvement in outcomes of clinical islet transplantation: 1999–2010. Diabetes Care. 2012;35:1436–45. Hering BJ, Bellin MD. Transplantation: Sustained benefits of islet transplants for T1DM. Nat Rev Endocrinol. 2015;11:572–4. Pagliuca FW, Melton DA. How to make a functional beta-cell. Development. 2013;140:2472–83. Ariyachet C, Tovaglieri A, Xiang G, et al. Reprogrammed stomach tissue as a renewable source of functional β cells for blood glucose regulation. Cell Stem Cell. 2016;18:1–12. This paper shows that cells of the antral stomach region of mice can be reprogrammed to a beta-cell fate and that bioengineered stomach organoid gafts with these cells can rescue hyperglycemia in diabetic mice. Blum B, Hrvatin SS, Schuetz C, Bonal C, Rezania A, Melton DA. Functional beta-cell maturation is marked by an increased glucose threshold and by expression of urocortin 3. Nat Biotechnol. 2012;30:261–4. Pagliuca FW, Millman JR, Gurtler M, et al. Generation of functional human pancreatic beta cells in vitro. Cell. 2014;159:428–39. This paper reports a scalable differentiation protocol for human pluripotent stem cells that can generate glucose-responsive beta-cells, which secrete human insulin and are able to ameliorate hyperglycemia after transplantation into diabetic mice. Rezania A, Bruin JE, Riedel MJ, et al. Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes. 2012;61:2016–29. Rezania A, Bruin JE, Xu J, et al. Enrichment of human embryonic stem cell-derived NKX6.1-expressing pancreatic progenitor cells accelerates the maturation of insulin-secreting cells in vivo. Stem Cells. 2013;31:2432–42. Vegas AJ, Veiseh O, Gurtler M, et al. Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med. 2016. doi:10.1038/nm.4030. This paper reports the first long-term correction of diabetes in immunocompetent mice by transplantation of human pluripotent stem cell-derived beta-cells encapsulated with alginate derivatives. Vegas AJ, Veiseh O, Doloff JC, et al. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat Biotechnol. 2016. doi:10.1038/nbt.3462. This study used a combinatorial approach for covalent chemical modifications of alginate and tested their biocompatibility in non-human primates. Agulnick AD, Ambruzs DM, Moorman MA, et al. Insulin-producing endocrine cells differentiated in vitro from human embryonic stem cells function in macroencapsulation devices in vivo. Stem Cells Transl Med. 2015;4:1214–22. Kobayashi T, Yamaguchi T, Hamanaka S, et al. Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell. 2010;142:787–99. Matsunari H, Nagashima H, Watanabe M, et al. Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs. Proc Natl Acad Sci U S A. 2013;110:4557–62. This paper reports the generation of allogeneic pig pancreas by complementation of pancreatogenesis-disabled pig blastocysts with intact embryonic blastomeres from a different genetic background. Masaki H, Kato-Itoh M, Umino A, et al. Interspecific in vitro assay for the chimera-forming ability of human pluripotent stem cells. Development. 2015;142:3222–30. Hermeren G. Ethical considerations in chimera research. Development. 2015;142:3–5. Kobayashi T, Kato-Itoh M, Nakauchi H. Targeted organ generation using Mixl1-inducible mouse pluripotent stem cells in blastocyst complementation. Stem Cells Dev. 2015;24:182–9. Wu J, Izpisua Belmonte JC. Dynamic pluripotent stem cell states and their applications. Cell Stem Cell. 2015;17:509–25. Excellent review of different strategies of interspecies chimeric complementation. Takebe T, Enomura M, Yoshizawa E, et al. Vascularized and complex organ buds from diverse tissues via mesenchymal cell-driven condensation. Cell Stem Cell. 2015;16:556–65. Yokote S, Matsunari H, Iwai S, et al. Urine excretion strategy for stem cell-generated embryonic kidneys. Proc Natl Acad Sci U S A. 2015;112:12980–5. Kemter E, Wolf E. Pigs pave a way to de novo formation of functional human kidneys. Proc Natl Acad Sci U S A. 2015;112:12905–6. Lee K, Kwon DN, Ezashi T, et al. Engraftment of human iPS cells and allogeneic porcine cells into pigs with inactivated RAG2 and accompanying severe combined immunodeficiency. Proc Natl Acad Sci U S A. 2014;111:7260–5. Dufrane D, Gianello P. Macro- or microencapsulation of pig islets to cure type 1 diabetes. World J Gastroenterol. 2012;18:6885–93. Nagaraju S, Bottino R, Wijkstrom M, Trucco M, Cooper DK. Islet xenotransplantation: what is the optimal age of the islet-source pig? Xenotransplantation. 2015;22:7–19. Cardona K, Korbutt GS, Milas Z, et al. Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med. 2006;12:304–6. Hering BJ, Wijkstrom M, Graham ML, et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med. 2006;12:301–3. Thompson P, Badell IR, Lowe M, et al. Alternative immunomodulatory strategies for xenotransplantation: CD40/154 pathway-sparing regimens promote xenograft survival. Am J Transplant. 2012;12:1765–75. Shin JS, Kim JM, Kim JS, et al. Long-term control of diabetes in immunosuppressed nonhuman primates (NHP) by the transplantation of adult porcine islets. Am J Transplant. 2015;15:2837–50. This paper describes the longest survival and function of wild-type pig islets in diabetic rhesus macaques with immunosuppression. Kawai T, Andrews D, Colvin RB, Sachs DH, Cosimi AB. Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med. 2000;6:114. Ludwig B, Ludwig S. Transplantable bioartificial pancreas devices: current status and future prospects. Langenbeck's Arch Surg. 2015;400:531–40. Robles L, Storrs R, Lamb M, Alexander M, Lakey JR. Current status of islet encapsulation. Cell Transplant. 2014;23:1321–48. Dufrane D, Goebbels RM, Saliez A, Guiot Y, Gianello P. Six-month survival of microencapsulated pig islets and alginate biocompatibility in primates: proof of concept. Transplantation. 2006;81:1345–53. Casu A, Bottino R, Balamurugan AN, et al. Metabolic aspects of pig-to-monkey (Macaca fascicularis) islet transplantation: implications for translation into clinical practice. Diabetologia. 2008;51:120–9. Dufrane D, Steenberghe M, Goebbels RM, Saliez A, Guiot Y, Gianello P. The influence of implantation site on the biocompatibility and survival of alginate encapsulated pig islets in rats. Biomaterials. 2006;27:3201–8. Yang HK, Ham DS, Park HS, et al. Long-term efficacy and biocompatibility of encapsulated islet transplantation with chitosan-coated alginate capsules in mice and canine models of diabetes. Transplantation. 2016;100:334–43. Matsumoto S, Tan P, Baker J, et al. Clinical porcine islet xenotransplantation under comprehensive regulation. Transplant Proc. 2014;46:1992–5. Wynyard S, Nathu D, Garkavenko O, Denner J, Elliott R. Microbiological safety of the first clinical pig islet xenotransplantation trial in New Zealand. Xenotransplantation. 2014;21:309–23. Hill RS, Cruise GM, Hager SR, et al. Immunoisolation of adult porcine islets for the treatment of diabetes mellitus. The use of photopolymerizable polyethylene glycol in the conformal coating of mass-isolated porcine islets. Ann N Y Acad Sci. 1997;831:332–43. Tomei AA, Manzoli V, Fraker CA, et al. Device design and materials optimization of conformal coating for islets of Langerhans. Proc Natl Acad Sci U S A. 2014;111:10514–9. This paper describes novel approaches and instruments for conformal coating of pancreatic islets. Dufrane D, Goebbels RM, Gianello P. Alginate macroencapsulation of pig islets allows correction of streptozotocin-induced diabetes in primates up to 6 months without immunosuppression. Transplantation. 2010;90:1054–62. Neufeld T, Ludwig B, Barkai U, et al. The efficacy of an immunoisolating membrane system for islet xenotransplantation in minipigs. PLoS One. 2013;8, e70150. Ludwig B, Reichel A, Steffen A, et al. Transplantation of human islets without immunosuppression. Proc Natl Acad Sci U S A. 2013;110:19054–8. This paper reports long-term survival of allogeneic human islets in an oxygenated chamber system transplanted in a type 1 diabetic patient without immunosuppression. Ludwig B, Rotem A, Schmid J, et al. Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist. Proc Natl Acad Sci U S A. 2012;109:5022–7. Ludwig B, Ludwig S, Steffen A, et al. Preclinical studies on porcine islet macroencapsulation in non-human primates. Xenotransplantation. 2015;22 Suppl 1:S19–20. Bottino R, Trucco M. Use of genetically-engineered pig donors in islet transplantation. World J Transplant. 2015;5:243–50. van der Windt DJ, Marigliano M, He J, et al. Early islet damage after direct exposure of pig islets to blood: has humoral immunity been underestimated? Cell Transplant. 2012;21:1791–802. Rayat GR, Rajotte RV, Hering BJ, Binette TM, Korbutt GS. In vitro and in vivo expression of Galalpha-(1,3)Gal on porcine islet cells is age dependent. J Endocrinol. 2003;177:127–35. van der Windt DJ, Bottino R, Casu A, et al. Long-term controlled normoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets. Am J Transplant. 2009;9:2716–26. Thompson P, Badell IR, Lowe M, et al. Islet xenotransplantation using gal-deficient neonatal donors improves engraftment and function. Am J Transplant. 2011;11:2593–602. Hawthorne WJ, Salvaris EJ, Phillips P, et al. Control of IBMIR in neonatal porcine islet xenotransplantation in baboons. Am J Transplant. 2014;14:1300–9. Martin BM, Samy KP, Lowe MC, et al. Dual islet transplantation modeling of the instant blood-mediated inflammatory reaction. Am J Transplant. 2015;15:1241–52. This paper describes an elegant transplantation model in rhesus macaques, where islets from two different sources are infused into distictly vascularized liver lobes and can thus be tested in the same recipient. Shapiro AM. Islet transplantation in type 1 diabetes: ongoing challenges, refined procedures, and long-term outcome. Rev Diabet Stud. 2012;9:385–406. Bertuzzi F, Marzorati S, Maffi P, et al. Tissue factor and CCL2/monocyte chemoattractant protein-1 released by human islets affect islet engraftment in type 1 diabetic recipients. J Clin Endocrinol Metab. 2004;89:5724–8. Lee I, Wang L, Wells AD, et al. Blocking the monocyte chemoattractant protein-1/CCR2 chemokine pathway induces permanent survival of islet allografts through a programmed death-1 ligand-1-dependent mechanism. J Immunol. 2003;171:6929–35. Moberg L, Johansson H, Lukinius A, et al. Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet. 2002;360:2039–45. Kourtzelis I, Magnusson PU, Kotlabova K, Lambris JD, Chavakis T. Regulation of instant blood mediated inflammatory reaction (IBMIR) in pancreatic islet xeno-transplantation: points for therapeutic interventions. Adv Exp Med Biol. 2015;865:171–88. Lu B, Rutledge BJ, Gu L, et al. Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med. 1998;187:601–8. Wood JP, Ellery PE, Maroney SA, Mast AE. Biology of tissue factor pathway inhibitor. Blood. 2014;123:2934–43. Soderlund J, Wennberg L, Castanos-Velez E, et al. Fetal porcine islet-like cell clusters transplanted to cynomolgus monkeys: an immunohistochemical study. Transplantation. 1999;67:784–91. Klymiuk N, van Buerck L, Bahr A, et al. Xenografted islet cell clusters from INSLEA29Y transgenic pigs rescue diabetes and prevent immune rejection in humanized mice. Diabetes. 2012;61:1527–32. This paper shows that local expression of LEA29Y in transgenic pig islet grafts prevents their rejection in mice with human immune cells. Wolf-van Buerck L, Schuster M, Baehr A, et al. Engraftment and reversal of diabetes after intramuscular transplantation of neonatal porcine islet-like clusters. Xenotransplantation. 2015;22:443–50. Plotzki E, Wolf-van Buerck L, Knauf Y, et al. Virus safety of islet cell transplantation from transgenic pigs to marmosets. Virus Res. 2015;204:95–102. Plege A, Borns K, Baars W, Schwinzer R. Suppression of human T-cell activation and expansion of regulatory T cells by pig cells overexpressing PD-ligands. Transplantation. 2009;87:975–82. Plege-Fleck A, Lieke T, Romermann D, et al. Pig to rat cell transplantation: reduced cellular and antibody responses to xenografts overexpressing PD-L1. Xenotransplantation. 2014;21:533–42. Yi S, Feng X, Hawthorne WJ, Patel AT, Walters SN, O'Connell PJ. CD4+ T cells initiate pancreatic islet xenograft rejection via an interferon-gamma-dependent recruitment of macrophages and natural killer cells. Transplantation. 2002;73:437–46. Weiss EH, Lilienfeld BG, Muller S, et al. HLA-E/human beta2-microglobulin transgenic pigs: protection against xenogeneic human anti-pig natural killer cell cytotoxicity. Transplantation. 2009;87:35–43. Byrne GW, McGregor CG, Breimer ME. Recent investigations into pig antigen and anti-pig antibody expression. Int J Surg. 2015;23:223–8. Bottino R, Hara H, Iwase H, et al. In vitro exposure of isolated porcine islets from Neu5Gc-knockout/GTknockout/hCD46 transgenic donors to human blood/plasma. Xenotransplantation. 2015;22 Suppl 1:S65–6. Park CG, Bottino R, Hawthorne WJ. Current status of islet xenotransplantation. Int J Surg. 2015;23:261–6. Wijkstrom M, Bottino R, Iwase H, et al. Glucose metabolism in pigs expressing human genes under an insulin promoter. Xenotransplantation. 2015;22:70–9. Bottino R, Wijkstrom M, van der Windt DJ, et al. Pig-to-monkey islet xenotransplantation using multi-transgenic pigs. Am J Transplant. 2014;14:2275–87. Emamaullee JA, Rajotte RV, Liston P, et al. XIAP overexpression in human islets prevents early posttransplant apoptosis and reduces the islet mass needed to treat diabetes. Diabetes. 2005;54:2541–8. Pepper AR, Gala-Lopez B, Pawlick R, Merani S, Kin T, Shapiro AMJ. A prevascularized subcutaneous device-less site for islet and cellular transplantation. Nat Biotechnol. 2015;33:518–23. Lai Y, Schneider D, Kidszun A, et al. Vascular endothelial growth factor increases functional beta-cell mass by improvement of angiogenesis of isolated human and murine pancreatic islets. Transplantation. 2005;79:1530–6. Zhang N, Richter A, Suriawinata J, et al. Elevated vascular endothelial growth factor production in islets improves islet graft vascularization. Diabetes. 2004;53:963–70. Klymiuk N, Bocker W, Schonitzer V, et al. First inducible transgene expression in porcine large animal models. FASEB J. 2012;26:1086–99. Speier S, Nyqvist D, Cabrera O, et al. Noninvasive in vivo imaging of pancreatic islet cell biology. Nat Med. 2008;14:574–8. Speier S, Nyqvist D, Kohler M, Caicedo A, Leibiger IB, Berggren PO. Noninvasive high-resolution in vivo imaging of cell biology in the anterior chamber of the mouse eye. Nat Protoc. 2008;3:1278–86. Mueller KR, Balamurugan AN, Cline GW, et al. Differences in glucose-stimulated insulin secretion in vitro of islets from human, nonhuman primate, and porcine origin. Xenotransplantation. 2013;20:75–81. Mourad N, Xhema D, Perota A, Galli C, Gianello P. Beta-cell-specific expression of glucagon-like peptide 1 (GLP-1) and activated muscarinic receptor (M3R) improves pig islet secretory function. Xenotransplantation. 2015;22 Suppl 1:S176. Denner J, Schuurman HJ, Patience C. The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--chapter 5: Strategies to prevent transmission of porcine endogenous retroviruses. Xenotransplantation. 2009;16:239–48. Denner J, Mueller NJ. Preventing transfer of infectious agents. Int J Surg. 2015;23:306–11. Yang L, Guell M, Niu D, et al. Genome-wide inactivation of porcine endogenous retroviruses (PERVs). Science (New York, NY). 2015;350:1101–4. This study used the CRISPR/Cas system to mutate all copies of the PERV pol gene in a porcine cell line. Cosgun KN, Rahmig S, Mende N, et al. Kit regulates HSC engraftment across the human-mouse species barrier. Cell Stem Cell. 2014;15:227–38. Renner S, Braun-Reichhart C, Blutke A, et al. Permanent neonatal diabetes in INS(C94Y) transgenic pigs. Diabetes. 2013;62:1505–11. This paper reports the first genetically diabetic pig model.