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Considerations Pertaining to Implant Sites for Cell-Based Insulin Replacement Therapies

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Pluripotent Stem Cell Therapy for Diabetes

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Abstract

Pancreatic islet transplantation (ITx) established proof of concept that cellular therapies are feasible options to manage intractable severe and recurrent hypoglycemia, but that they can also provide optimal glycemic control and insulin independence in a large proportion of patients. Long-term evidence is consolidating ITx as a safe and effective therapeutic alternative within the repertoire available for advanced diabetes management. Currently, clinical ITx encompasses islet isolation from deceased-donor pancreata followed by infusion of purified islets into the liver intraportal circulation. While evidence regarding the safety of intraportal islet delivery has been accruing over recent years, there are small potential risks with this implantation procedure, including bleeding and thrombosis. Moreover, there are unanswered questions regarding the implications of the immunological milieu on islet engraftment and early/long-term survival, the capacity to support physiological responses to stimuli, and its potential to accommodate novel technologies, including cellular encapsulation and stem cell-based therapies. Although research into further characterizing the intraportal implantation site is ongoing, endeavors evaluating extrahepatic implantation sites are also actively being explored in an attempt to circumvent some of the limitations with the intraportal site. In this chapter, we focus on discussing implantation sites and techniques, and potential implications for current and future β-cell replacement therapies. We synthesize key physiological concepts and elaborate on aspects regarding graft survival and function. Finally, we succinctly review the current clinical evidence on intraportal and extrahepatic implantation sites and suggest potential research avenues to be explored in the future.

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References

  1. Abdulreda, M. H., Faleo, G., Molano, R. D., Lopez-Cabezas, M., Molina, J., Tan, Y., Echeverria, O. A., Zahr-Akrawi, E., Rodriguez-Diaz, R., Edlund, P. K., Leibiger, I., Bayer, A. L., Perez, V., Ricordi, C., Caicedo, A., Pileggi, A. & Berggren, P. O. 2011. High-resolution, noninvasive longitudinal live imaging of immune responses. Proc Natl Acad Sci U S A, 108, 12863–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Alwafi, H., Alsharif, A. A., Wei, L., Langan, D., Naser, A. Y., Mongkhon, P., Bell, J. S., Ilomaki, J., Al Metwazi, M. S., Man, K. K. C., Fang, G. & Wong, I. C. K. 2020. Incidence and prevalence of hypoglycaemia in type 1 and type 2 diabetes individuals: A systematic review and meta-analysis. Diabetes Res Clin Pract, 170, 108522.

    Article  PubMed  Google Scholar 

  3. Anteby, R., Lucander, A., Bachul, P. J., Pyda, J., Grybowski, D., Basto, L., Generette, G. S., Perea, L., Golab, K., Wang, L. J., Tibudan, M., Thomas, C., Fung, J. & Witkowski, P. 2021. Evaluating the Prognostic Value of Islet Autoantibody Monitoring in Islet Transplant Recipients with Long-Standing Type 1 Diabetes Mellitus. J Clin Med, 10.

    Google Scholar 

  4. Aragón, F., Karaca, M., Novials, A., Maldonado, R., Maechler, P. & Rubí, B. 2015. Pancreatic polypeptide regulates glucagon release through PPYR1 receptors expressed in mouse and human alpha-cells. Biochim Biophys Acta, 1850, 343–51.

    Article  PubMed  Google Scholar 

  5. Arias-Diaz, J., Vara, E., Balibrea, J. L., Garcia, C., Maranes, A., Diaz, A., Lezana, A. H., Gallego, J., Rodriguez, R., Maranes, J. P. & Barrientos, A. 1996. CT-guided fine-needle approach for intrathymic islet transplantation in a diabetic patient. Pancreas, 12, 100–2.

    Article  PubMed  CAS  Google Scholar 

  6. Arifin, D. R., Valdeig, S., Anders, R. A., Bulte, J. W. & Weiss, C. R. 2016. Magnetoencapsulated human islets xenotransplanted into swine: a comparison of different transplantation sites. Xenotransplantation, 23, 211–21.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Arzouni, A. A., Vargas-Seymour, A., Nardi, N., King, A. J. F. & Jones, P. M. 2018. Using Mesenchymal Stromal Cells in Islet Transplantation. Stem Cells Transl Med, 7, 559–563.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Atkinson, M. A. & Eisenbarth, G. S. 2001. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet, 358, 221–9.

    Article  PubMed  CAS  Google Scholar 

  9. Atkinson, M. A., Eisenbarth, G. S. & Michels, A. W. 2014. Type 1 diabetes. Lancet, 383, 69–82.

    Article  PubMed  Google Scholar 

  10. Bachul, P., Generette, G., Perez-Gutierrez, A., Borek, P., Wang, L., Golab, K., Basto, L., Perea, L., Tibudan, M., Juengel, B., Kumar, J., Thomas, C., Philipson, L., Fung, J. & Witkowski, P. 307.5 Modified approach allowed for improved islet allotransplantation into pre-vascularized Sernova Cell PouchTM device - preliminary results of the phase I/II clinical trial at University of Chicago. IPITA Virtual Congress 2021, 2021 Virtual.

    Google Scholar 

  11. Baidal, D., Rickels, M., Ballou, C., Payne, E., Barton, F. & Alejandro, R. 2021. Predictive Value of C-peptide Measures for Clinical Outcomes of Islet Transplantation in Type 1 Diabetes: A Report From the Collaborative Islet Transplant Registry (CITR). Transplantation, 105, S4.

    Article  Google Scholar 

  12. Baidal, D. A., Ricordi, C., Berman, D. M., Alvarez, A., Padilla, N., Ciancio, G., Linetsky, E., Pileggi, A. & Alejandro, R. 2017. Bioengineering of an Intraabdominal Endocrine Pancreas. N Engl J Med, 376, 1887–1889.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Balamurugan, A. N., Naziruddin, B., Lockridge, A., Tiwari, M., Loganathan, G., Takita, M., Matsumoto, S., Papas, K., Trieger, M., Rainis, H., Kin, T., Kay, T. W., Wease, S., Messinger, S., Ricordi, C., Alejandro, R., Markmann, J., Kerr-Conti, J., Rickels, M. R., Liu, C., Zhang, X., Witkowski, P., Posselt, A., Maffi, P., Secchi, A., Berney, T., O’Connell, P. J., Hering, B. J. & Barton, F. B. 2014. Islet product characteristics and factors related to successful human islet transplantation from the Collaborative Islet Transplant Registry (CITR) 1999-2010. Am J Transplant, 14, 2595–606.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Barrett, K. E., Barman, S. M., Boitano, S. & Brooks, H. L. 2018. Editors. Ganong’s Review of Medical Physiology, 25e. New York, NY: McGraw-Hill Education.

    Google Scholar 

  15. Bartholomeus, K., Jacobs-Tulleneers-Thevissen, D., Shouyue, S., Suenens, K., In’t Veld, P. A., Pipeleers-Marichal, M., Pipeleers, D. G. & Hellemans, K. 2013. Omentum is better site than kidney capsule for growth, differentiation, and vascularization of immature porcine beta-cell implants in immunodeficient rats. Transplantation, 96, 1026–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Barton, F. B., Rickels, M. R., Alejandro, R., Hering, B. J., Wease, S., Naziruddin, B., Oberholzer, J., Odorico, J. S., Garfinkel, M. R., Levy, M., Pattou, F., Berney, T., Secchi, A., Messinger, S., Senior, P. A., Maffi, P., Posselt, A., Stock, P. G., Kaufman, D. B., Luo, X., Kandeel, F., Cagliero, E., Turgeon, N. A., Witkowski, P., Naji, A., O’Connell, P. J., Greenbaum, C., Kudva, Y. C., Brayman, K. L., Aull, M. J., Larsen, C., Kay, T. W., Fernandez, L. A., Vantyghem, M. C., Bellin, M. & Shapiro, A. M. 2012. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care, 35, 1436–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Bellin, M. D., Barton, F. B., Heitman, A., Harmon, J. V., Kandaswamy, R., Balamurugan, A. N., Sutherland, D. E., Alejandro, R. & Hering, B. J. 2012. Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant, 12, 1576–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Belz, G. T., Behrens, G. M., Smith, C. M., Miller, J. F., Jones, C., Lejon, K., Fathman, C. G., Mueller, S. N., Shortman, K., Carbone, F. R. & Heath, W. R. 2002. The CD8alpha(+) dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens. J Exp Med, 196, 1099–104.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Bertuzzi, F., Colussi, G., Lauterio, A. & De Carlis, L. 2018. Intramuscular islet allotransplantation in type 1 diabetes mellitus. Eur Rev Med Pharmacol Sci, 22, 1731–1736.

    PubMed  CAS  Google Scholar 

  20. Bhargava, R., Senior, P. A., Ackerman, T. E., Ryan, E. A., Paty, B. W., Lakey, J. R. & Shapiro, A. M. 2004. Prevalence of hepatic steatosis after islet transplantation and its relation to graft function. Diabetes, 53, 1311–7.

    Article  PubMed  CAS  Google Scholar 

  21. Blake, D. F., Young, D. A. & Brown, L. H. 2018. Transcutaneous oximetry: variability in normal values for the upper and lower limb. Diving Hyperb Med, 48, 2–9.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bochenek, M. A., Veiseh, O., Vegas, A. J., Mcgarrigle, J. J., Qi, M., Marchese, E., Omami, M., Doloff, J. C., Mendoza-Elias, J., Nourmohammadzadeh, M., Khan, A., Yeh, C. C., **ng, Y., Isa, D., Ghani, S., Li, J., Landry, C., Bader, A. R., Olejnik, K., Chen, M., Hollister-Lock, J., Wang, Y., Greiner, D. L., Weir, G. C., Strand, B. L., Rokstad, A. M. A., Lacik, I., Langer, R., Anderson, D. G. & Oberholzer, J. 2018. Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques. Nat Biomed Eng, 2, 810–821.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Borg, D. J., Weigelt, M., Wilhelm, C., Gerlach, M., Bickle, M., Speier, S., Bonifacio, E. & Hommel, A. 2014. Mesenchymal stromal cells improve transplanted islet survival and islet function in a syngeneic mouse model. Diabetologia, 57, 522–31.

    Article  PubMed  Google Scholar 

  24. Bosi, E., Bottazzo, G. F., Secchi, A., Pozza, G., Shattock, M., Saunders, A., Gelet, A., Touraine, J. L., Traeger, J. & Dubernard, J. M. 1989. Islet cell autoimmunity in type I diabetic patients after HLA-mismatched pancreas transplantation. Diabetes, 38 Suppl 1, 82–4.

    Article  PubMed  Google Scholar 

  25. Bosi, E., Braghi, S., Maffi, P., Scirpoli, M., Bertuzzi, F., Pozza, G., Secchi, A. & Bonifacio, E. 2001. Autoantibody response to islet transplantation in type 1 diabetes. Diabetes, 50, 2464–71.

    Article  PubMed  CAS  Google Scholar 

  26. Boucher, A. A., Wastvedt, S., Hodges, J. S., Beilman, G. J., Kirchner, V. A., Pruett, T. L., Hering, B. J., Schwarzenberg, S. J., Downs, E., Freeman, M., Trikudanathan, G., Chinnakotla, S. & Bellin, M. D. 2021. Portal Vein Thrombosis May Be More Strongly Associated With Islet Infusion Than Extreme Thrombocytosis After Total Pancreatectomy With Islet Autotransplantation. Transplantation, 105, 2499–2506.

    Article  PubMed  CAS  Google Scholar 

  27. Boyko, E. J., Ahroni, J. H. & Stensel, V. L. 2001. Tissue oxygenation and skin blood flow in the diabetic foot: responses to cutaneous warming. Foot Ankle Int, 22, 711–4.

    Article  PubMed  CAS  Google Scholar 

  28. Brissova, M., Shostak, A., Shiota, M., Wiebe, P. O., Poffenberger, G., Kantz, J., Chen, Z., Carr, C., Jerome, W. G., Chen, J., Baldwin, H. S., Nicholson, W., Bader, D. M., Jetton, T., Gannon, M. & Powers, A. C. 2006. Pancreatic islet production of vascular endothelial growth factor--a is essential for islet vascularization, revascularization, and function. Diabetes, 55, 2974–85.

    Google Scholar 

  29. Buchwald, P., Tamayo-Garcia, A., Manzoli, V., Tomei, A. A. & Stabler, C. L. 2018. Glucose-stimulated insulin release: Parallel perifusion studies of free and hydrogel encapsulated human pancreatic islets. Biotechnol Bioeng, 115, 232–245.

    Article  PubMed  CAS  Google Scholar 

  30. Bulek, A. M., Cole, D. K., Skowera, A., Dolton, G., Gras, S., Madura, F., Fuller, A., Miles, J. J., Gostick, E., Price, D. A., Drijfhout, J. W., Knight, R. R., Huang, G. C., Lissin, N., Molloy, P. E., Wooldridge, L., Jakobsen, B. K., Rossjohn, J., Peakman, M., Rizkallah, P. J. & Sewell, A. K. 2012. Structural basis for the killing of human beta cells by CD8(+) T cells in type 1 diabetes. Nat Immunol, 13, 283–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Calafiore, R. 1992. Transplantation of microencapsulated pancreatic human islets for therapy of diabetes mellitus. A preliminary report. ASAIO J, 38, 34–7.

    Article  PubMed  CAS  Google Scholar 

  32. Calderon, B., Suri, A., Miller, M. J. & Unanue, E. R. 2008. Dendritic cells in islets of Langerhans constitutively present beta cell-derived peptides bound to their class II MHC molecules. Proc Natl Acad Sci U S A, 105, 6121–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Calderon, B., Suri, A. & Unanue, E. R. 2006. In CD4+ T-cell-induced diabetes, macrophages are the final effector cells that mediate islet beta-cell killing: studies from an acute model. Am J Pathol, 169, 2137–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Cantarelli, E., Melzi, R., Mercalli, A., Sordi, V., Ferrari, G., Lederer, C. W., Mrak, E., Rubinacci, A., Ponzoni, M., Sitia, G., Guidotti, L. G., Bonifacio, E. & Piemonti, L. 2009. Bone marrow as an alternative site for islet transplantation. Blood, 114, 4566–74.

    Article  PubMed  CAS  Google Scholar 

  35. Cantarelli, E. & Piemonti, L. 2011. Alternative transplantation sites for pancreatic islet grafts. Curr Diab Rep, 11, 364–74.

    Article  PubMed  Google Scholar 

  36. Carlessi, R., Chen, Y., Rowlands, J., Cruzat, V. F., Keane, K. N., Egan, L., Mamotte, C., Stokes, R., Gunton, J. E., Bittencourt, P. I. H. & Newsholme, P. 2017. GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation. Sci Rep, 7, 2661.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Chen, J., Cheng, Y., Fu, Y., Zhao, H., Tang, M., Lin, N., Shi, X., Lei, Y., Wang, S., Huang, L., Wu, W. & Tan, J. 2020. Mesenchymal stem cell-derived exosomes protect beta cells against hypoxia-induced apoptosis via miR-21 by alleviating ER stress and inhibiting p38 MAPK phosphorylation. Stem Cell Res Ther, 11, 97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Choudhary, P., Rickels, M. R., Senior, P. A., Vantyghem, M. C., Maffi, P., Kay, T. W., Keymeulen, B., Inagaki, N., Saudek, F., Lehmann, R. & Hering, B. J. 2015. Evidence-informed clinical practice recommendations for treatment of type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care, 38, 1016–29.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Christensen, M., Vedtofte, L., Holst, J. J., Vilsbøll, T. & Knop, F. K. 2011. Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes, 60, 3103–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Christiansen, E., Tibell, A., Volund, A., Rasmussen, K., Groth, C. G., Holst, J. J., Pedersen, O., Christensen, N. J. & Madsbad, S. 1996. Pancreatic endocrine function in recipients of segmental and whole pancreas transplantation. J Clin Endocrinol Metab, 81, 3972–9.

    PubMed  CAS  Google Scholar 

  41. Christoffersson, G., Henriksnas, J., Johansson, L., Rolny, C., Ahlstrom, H., Caballero-Corbalan, J., Segersvard, R., Permert, J., Korsgren, O., Carlsson, P. O. & Phillipson, M. 2010. Clinical and experimental pancreatic islet transplantation to striated muscle: establishment of a vascular system similar to that in native islets. Diabetes, 59, 2569–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. CITR 2017. Tenth Annual Report. In: Center, C. C. (ed.). Collaborative Islet Transplant Registry.

    Google Scholar 

  43. Coronel, M. M., Liang, J. P., Li, Y. & Stabler, C. L. 2019. Oxygen generating biomaterial improves the function and efficacy of beta cells within a macroencapsulation device. Biomaterials, 210, 1–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Cryer, P. E. 2014. Glycemic goals in diabetes: trade-off between glycemic control and iatrogenic hypoglycemia. Diabetes, 63, 2188–95.

    Article  PubMed  Google Scholar 

  45. Cuesta-Gomez, N., Graham, G. J. & Campbell, J. D. M. 2021. Chemokines and their receptors: predictors of the therapeutic potential of mesenchymal stromal cells. J Transl Med, 19, 156.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Cuesta-Gomez, N., Verhoeff, K., Jasra, I. T., Pawlick, R., Dadheech, N. & Shapiro, A. M. J. 2022. Characterization of stem-cell-derived islets during differentiation and after implantation. Cell Rep, 40, 111238.

    Article  PubMed  CAS  Google Scholar 

  47. Cugnenc, P. H., Bethoux, J. P., Altman, J. J., Bismuth, H., Wind, P., Drevillon, C., Tessier, C., Moulonguet, L. & Chretien, Y. 1990. [Implantation of pancreatic islets in arteriolar epiploic flap. Preliminary note on 3 cases]. Chirurgie, 116, 268–74.

    PubMed  CAS  Google Scholar 

  48. Da Silva Xavier, G. 2018. The Cells of the Islets of Langerhans. J Clin Med, 7.

    Google Scholar 

  49. Danke, N. A., Yang, J., Greenbaum, C. & Kwok, W. W. 2005. Comparative study of GAD65-specific CD4+ T cells in healthy and type 1 diabetic subjects. J Autoimmun, 25, 303–11.

    Article  PubMed  CAS  Google Scholar 

  50. De Mesquita, G. H. A., Jardim, Y. J., Iuamoto, L. R., Suguita, F. Y., Essu, F. F., Oliveira, L. T., Meyer, A., Crescenzi, A., Rocha-Santos, V., Galvao, F. H. F., Andraus, W., Chaib, E. & D’Albuquerque, L. A. C. 2018. Gastric fundus submucosa as a site for islets transplantation: An experimental study. Ann Med Surg (Lond), 28, 1–5.

    Article  PubMed  Google Scholar 

  51. Desai, N. M., Goss, J. A., Deng, S., Wolf, B. A., Markmann, E., Palanjian, M., Shock, A. P., Feliciano, S., Brunicardi, F. C., Barker, C. F., Naji, A. & Markmann, J. F. 2003. Elevated portal vein drug levels of sirolimus and tacrolimus in islet transplant recipients: local immunosuppression or islet toxicity? Transplantation, 76, 1623–5.

    Article  PubMed  CAS  Google Scholar 

  52. Dilorenzo, T. P. 2011. Multiple antigens versus single major antigen in type 1 diabetes: arguing for multiple antigens. Diabetes Metab Res Rev, 27, 778–83.

    Article  PubMed  CAS  Google Scholar 

  53. Dimeglio, L. A., Evans-Molina, C. & Oram, R. A. 2018. Type 1 diabetes. Lancet, 391, 2449–2462.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Dionne, K. E., Colton, C. K. & Yarmush, M. L. 1993. Effect of hypoxia on insulin secretion by isolated rat and canine islets of Langerhans. Diabetes, 42, 12–21.

    Article  PubMed  CAS  Google Scholar 

  55. Dirnena-Fusini, I., Am, M. K., Fougner, A. L., Carlsen, S. M. & Christiansen, S. C. 2021. Physiological effects of intraperitoneal versus subcutaneous insulin infusion in patients with diabetes mellitus type 1: A systematic review and meta-analysis. PLoS One, 16, e0249611.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Du Toit, D. F., Reece-Smith, H., Mcshane, P., Denton, T. & Morris, P. J. 1982. Effect of cyclosporin A on allotransplanted pancreatic fragments to the spleen of totally pancreatectomized dogs. Transplantation, 33, 302–7.

    Article  PubMed  Google Scholar 

  57. Echeverri, G. J., Mcgrath, K., Bottino, R., Hara, H., Dons, E. M., Van Der Windt, D. J., Ekser, B., Casu, A., Houser, S., Ezzelarab, M., Wagner, R., Trucco, M., Lakkis, F. G. & Cooper, D. K. 2009. Endoscopic gastric submucosal transplantation of islets (ENDO-STI): technique and initial results in diabetic pigs. Am J Transplant, 9, 2485–96.

    Article  PubMed  CAS  Google Scholar 

  58. Eich, T., Eriksson, O., Lundgren, T. & Nordic Network for Clinical Islet, T. 2007. Visualization of early engraftment in clinical islet transplantation by positron-emission tomography. N Engl J Med, 356, 2754–5.

    Article  PubMed  CAS  Google Scholar 

  59. Eriksson, O., Eich, T., Sundin, A., Tibell, A., Tufveson, G., Andersson, H., Felldin, M., Foss, A., Kyllönen, L., Langstrom, B., Nilsson, B., Korsgren, O. & Lundgren, T. 2009. Positron emission tomography in clinical islet transplantation. Am J Transplant, 9, 2816–24.

    Article  PubMed  CAS  Google Scholar 

  60. Ferreira, L. M. R., Muller, Y. D., Bluestone, J. A. & Tang, Q. 2019. Next-generation regulatory T cell therapy. Nat Rev Drug Discov, 18, 749–769.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Frank, A., Deng, S., Huang, X., Velidedeoglu, E., Bae, Y. S., Liu, C., Abt, P., Stephenson, R., Mohiuddin, M., Thambipillai, T., Markmann, E., Palanjian, M., Sellers, M., Naji, A., Barker, C. F. & Markmann, J. F. 2004. Transplantation for type I diabetes: comparison of vascularized whole-organ pancreas with isolated pancreatic islets. Ann Surg, 240, 631–40; discussion 640–3.

    Article  PubMed  Google Scholar 

  62. Fukuda, S., Yabe, S. G., Nishida, J., Takeda, F., Nashiro, K. & Okochi, H. 2019. The intraperitoneal space is more favorable than the subcutaneous one for transplanting alginate fiber containing iPS-derived islet-like cells. Regen Ther, 11, 65–72.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Fung, M., Thompson, D., Shapiro, R. J., Warnock, G. L., Andersen, D. K., Elahi, D. & Meneilly, G. S. 2006. Effect of glucagon-like peptide-1 (7-37) on beta-cell function after islet transplantation in type 1 diabetes. Diabetes Res Clin Pract, 74, 189–93.

    Article  PubMed  CAS  Google Scholar 

  64. Gala-Lopez, B., Pepper, A. R., Dinyari, P., Malcolm, A., Kin, T., Pawlick, R., Senior, P. A. & Shapiro, A. M. 2016. Subcutaneous clinical islet transplanta on in a prevascularized subcutaneous pouch – preliminary experience. CellR4, 4, e2132.

    Google Scholar 

  65. Gerber, P. A. & Rutter, G. A. 2017. The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus. Antioxid Redox Signal, 26, 501–518.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Goswami, D., Domingo-Lopez, D. A., Ward, N. A., Millman, J. R., Duffy, G. P., Dolan, E. B. & Roche, E. T. 2021. Design Considerations for Macroencapsulation Devices for Stem Cell Derived Islets for the Treatment of Type 1 Diabetes. Adv Sci (Weinh), 8, e2100820.

    Article  PubMed  Google Scholar 

  67. Greenbaum, C. J., Prigeon, R. L. & D’Alessio, D. A. 2002. Impaired beta-cell function, incretin effect, and glucagon suppression in patients with type 1 diabetes who have normal fasting glucose. Diabetes, 51, 951–7.

    Article  PubMed  CAS  Google Scholar 

  68. Gregory, G. A., Robinson, T. I. G., Linklater, S. E., Wang, F., Colagiuri, S., De Beaufort, C., Donaghue, K. C., International Diabetes Federation Diabetes Atlas Type 1 Diabetes in Adults Special Interest, G., Magliano, D. J., Maniam, J., Orchard, T. J., Rai, P. & Ogle, G. D. 2022. Global incidence, prevalence, and mortality of type 1 diabetes in 2021 with projection to 2040: a modelling study. Lancet Diabetes Endocrinol, 10, 741–760.

    Article  PubMed  Google Scholar 

  69. Groth, C. G. 1995. Transplantation of porcine fetal pancreas to diabetic patients. Lancet, 345, 735.

    Article  PubMed  CAS  Google Scholar 

  70. Gupta, V., Wahoff, D. C., Rooney, D. P., Poitout, V., Sutherland, D. E., Kendall, D. M. & Robertson, R. P. 1997. The defective glucagon response from transplanted intrahepatic pancreatic islets during hypoglycemia is transplantation site-determined. Diabetes, 46, 28–33.

    Article  PubMed  CAS  Google Scholar 

  71. Gur, C., Porgador, A., Elboim, M., Gazit, R., Mizrahi, S., Stern-Ginossar, N., Achdout, H., Ghadially, H., Dor, Y., Nir, T., Doviner, V., Hershkovitz, O., Mendelson, M., Naparstek, Y. & Mandelboim, O. 2010. The activating receptor NKp46 is essential for the development of type 1 diabetes. Nat Immunol, 11, 121–8.

    Article  PubMed  CAS  Google Scholar 

  72. Gutierrez, G. D., Gromada, J. & Sussel, L. 2017. Heterogeneity of the Pancreatic Beta Cell. Front Genet, 8, 22.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Hampton, R. F., Jimenez-Gonzalez, M. & Stanley, S. A. 2022. Unravelling innervation of pancreatic islets. Diabetologia, 65, 1069–1084.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Harden, P. N., Game, D. S., Sawitzki, B., Van Der Net, J. B., Hester, J., Bushell, A., Issa, F., Brook, M. O., Alzhrani, A., Schlickeiser, S., Scotta, C., Petchey, W., Streitz, M., Blancho, G., Tang, Q., Markmann, J., Lechler, R. I., Roberts, I. S. D., Friend, P. J., Hilton, R., Geissler, E. K., Wood, K. J. & Lombardi, G. 2021. Feasibility, long-term safety, and immune monitoring of regulatory T cell therapy in living donor kidney transplant recipients. Am J Transplant, 21, 1603–1611.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Hayward, J. A., Ellis, C. E., Seeberger, K., Lee, T., Salama, B., Mulet-Sierra, A., Kuppan, P., Adesida, A. & Korbutt, G. S. 2017. Cotransplantation of Mesenchymal Stem Cells With Neonatal Porcine Islets Improve Graft Function in Diabetic Mice. Diabetes, 66, 1312–1321.

    Article  PubMed  CAS  Google Scholar 

  76. Hellman, B., Salehi, A., Gylfe, E., Dansk, H. & Grapengiesser, E. 2009. Glucose generates coincident insulin and somatostatin pulses and antisynchronous glucagon pulses from human pancreatic islets. Endocrinology, 150, 5334–40.

    Article  PubMed  CAS  Google Scholar 

  77. Henriksnas, J., Lau, J., Zang, G., Berggren, P. O., Kohler, M. & Carlsson, P. O. 2012. Markedly decreased blood perfusion of pancreatic islets transplanted intraportally into the liver: disruption of islet integrity necessary for islet revascularization. Diabetes, 61, 665–73.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Hering, B. J., Ballou, C. M., Bellin, M. D., Payne, E. H., Kandeel, F., Witkowski, P., Alejandro, R., Rickels, M. R. & Barton, F. B. 2022. Factors associated with favourable 5 year outcomes in islet transplant alone recipients with type 1 diabetes complicated by severe hypoglycaemia in the Collaborative Islet Transplant Registry. Diabetologia.

    Google Scholar 

  79. Hicks, G., George, R. & Sywak, M. 2017. Short and long-term impact of parathyroid autotransplantation on parathyroid function after total thyroidectomy. Gland Surg, 6, S75–S85.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Hilbrands, R., Huurman, V. A., Gillard, P., Velthuis, J. H., De Waele, M., Mathieu, C., Kaufman, L., Pipeleers-Marichal, M., Ling, Z., Movahedi, B., Jacobs-Tulleneers-Thevissen, D., Monbaliu, D., Ysebaert, D., Gorus, F. K., Roep, B. O., Pipeleers, D. G. & Keymeulen, B. 2009. Differences in baseline lymphocyte counts and autoreactivity are associated with differences in outcome of islet cell transplantation in type 1 diabetic patients. Diabetes, 58, 2267–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Huang, H. H., Harrington, S. & Stehno-Bittel, L. 2018. The Flaws and Future of Islet Volume Measurements. Cell Transplant, 27, 1017–1026.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Huurman, V. A., Hilbrands, R., Pinkse, G. G., Gillard, P., Duinkerken, G., Van De Linde, P., Van Der Meer-Prins, P. M., Versteeg-Van Der Voort Maarschalk, M. F., Verbeeck, K., Alizadeh, B. Z., Mathieu, C., Gorus, F. K., Roelen, D. L., Claas, F. H., Keymeulen, B., Pipeleers, D. G. & Roep, B. O. 2008. Cellular islet autoimmunity associates with clinical outcome of islet cell transplantation. PLoS One, 3, e2435.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Insel, R. A., Dunne, J. L., Atkinson, M. A., Chiang, J. L., Dabelea, D., Gottlieb, P. A., Greenbaum, C. J., Herold, K. C., Krischer, J. P., Lernmark, Å., Ratner, R. E., Rewers, M. J., Schatz, D. A., Skyler, J. S., Sosenko, J. M. & Ziegler, A. G. 2015. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care, 38, 1964–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Ionescu-Tirgoviste, C., Gagniuc, P. A., Gubceac, E., Mardare, L., Popescu, I., Dima, S. & Militaru, M. 2015. A 3D map of the islet routes throughout the healthy human pancreas. Sci Rep, 5, 14634.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Jackson, S., Mager, D. R., Bhargava, R., Ackerman, T., Imes, S., Hubert, G., Koh, A., Shapiro, A. M. & Senior, P. A. 2013. Long-term follow-up of hepatic ultrasound findings in subjects with magnetic resonance imaging defined hepatic steatosis following clinical islet transplantation: a case-control study. Islets, 5, 16–21.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Jaeckel, E., Lipes, M. A. & Von Boehmer, H. 2004. Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes. Nat Immunol, 5, 1028–35.

    Article  PubMed  CAS  Google Scholar 

  87. Jansson, L. & Carlsson, P. O. 2019. Pancreatic Blood Flow with Special Emphasis on Blood Perfusion of the Islets of Langerhans. Compr Physiol, 9, 799–837.

    Article  PubMed  Google Scholar 

  88. Jeyagaran, A., Lu, C. E., Zbinden, A., Birkenfeld, A. L., Brucker, S. Y. & Layland, S. L. 2022. Type 1 diabetes and engineering enhanced islet transplantation. Adv Drug Deliv Rev, 189, 114481.

    Article  PubMed  CAS  Google Scholar 

  89. Jiang, K., Weaver, J. D., Li, Y., Chen, X., Liang, J. & Stabler, C. L. 2017. Local release of dexamethasone from macroporous scaffolds accelerates islet transplant engraftment by promotion of anti-inflammatory M2 macrophages. Biomaterials, 114, 71–81.

    Article  PubMed  CAS  Google Scholar 

  90. **dal, R. M., Sidner, R. A., Mcdaniel, H. B., Johnson, M. S. & Fineberg, S. E. 1998. Intraportal vs kidney subcapsular site for human pancreatic islet transplantation. Transplant Proc, 30, 398–9.

    Article  PubMed  CAS  Google Scholar 

  91. Kanak, M. A., Takita, M., Kunnathodi, F., Lawrence, M. C., Levy, M. F. & Naziruddin, B. 2014. Inflammatory response in islet transplantation. Int J Endocrinol, 2014, 451035.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Kawahara, T., Kin, T., Kashkoush, S., Gala-Lopez, B., Bigam, D. L., Kneteman, N. M., Koh, A., Senior, P. A. & Shapiro, A. M. 2011. Portal vein thrombosis is a potentially preventable complication in clinical islet transplantation. Am J Transplant, 11, 2700–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Kelley, D. E., Henry, R. R. & Edelman, S. V. 1996. Acute effects of intraperitoneal versus subcutaneous insulin delivery on glucose homeostasis in patients with NIDDM. Veterans Affairs Implantable Insulin Pump Study Group. Diabetes Care, 19, 1237–42.

    Article  PubMed  CAS  Google Scholar 

  94. Kendall, D. M., Teuscher, A. U. & Robertson, R. P. 1997. Defective glucagon secretion during sustained hypoglycemia following successful islet allo- and autotransplantation in humans. Diabetes, 46, 23–7.

    Article  PubMed  CAS  Google Scholar 

  95. Kerby, A., Jones, E. S., Jones, P. M. & King, A. J. 2013. Co-transplantation of islets with mesenchymal stem cells in microcapsules demonstrates graft outcome can be improved in an isolated-graft model of islet transplantation in mice. Cytotherapy, 15, 192–200.

    Article  PubMed  CAS  Google Scholar 

  96. Kim, H. I., Yu, J. E., Park, C. G. & Kim, S. J. 2010. Comparison of four pancreatic islet implantation sites. J Korean Med Sci, 25, 203–10.

    Article  PubMed  CAS  Google Scholar 

  97. Kim, J. M., Shin, J. S., Min, B. H., Kang, S. J., Yoon, I. H., Chung, H., Kim, J., Hwang, E. S., Ha, J. & Park, C. G. 2019. JAK3 inhibitor-based immunosuppression in allogeneic islet transplantation in cynomolgus monkeys. Islets, 11, 119–128.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Kin, T. 2010. Islet isolation for clinical transplantation. Adv Exp Med Biol, 654, 683–710.

    Article  PubMed  CAS  Google Scholar 

  99. Kissler, H. J., Niland, J. C., Olack, B., Ricordi, C., Hering, B. J., Naji, A., Kandeel, F., Oberholzer, J., Fernandez, L., Contreras, J., Stiller, T., Sowinski, J. & Kaufman, D. B. 2010. Validation of methodologies for quantifying isolated human islets: an Islet Cell Resources study. Clin Transplant, 24, 236–42.

    Article  PubMed  CAS  Google Scholar 

  100. Koehler, N., Buhler, L., Egger, B. & Gonelle-Gispert, C. 2022. Multipotent Mesenchymal Stromal Cells Interact and Support Islet of Langerhans Viability and Function. Front Endocrinol (Lausanne), 13, 822191.

    Article  PubMed  Google Scholar 

  101. Koh, A., Senior, P., Salam, A., Kin, T., Imes, S., Dinyari, P., Malcolm, A., Toso, C., Nilsson, B., Korsgren, O. & Shapiro, A. M. 2010. Insulin-heparin infusions peritransplant substantially improve single-donor clinical islet transplant success. Transplantation, 89, 465–71.

    Article  PubMed  CAS  Google Scholar 

  102. Komatsu, H., Kandeel, F. & Mullen, Y. 2018. Impact of Oxygen on Pancreatic Islet Survival. Pancreas, 47, 533–543.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Korsgren, O. 2017. Islet Encapsulation: Physiological Possibilities and Limitations. Diabetes, 66, 1748–1754.

    Article  PubMed  CAS  Google Scholar 

  104. Korsgren, O., Nilsson, B., Berne, C., Felldin, M., Foss, A., Kallen, R., Lundgren, T., Salmela, K., Tibell, A. & Tufveson, G. 2005. Current status of clinical islet transplantation. Transplantation, 79, 1289–93.

    Article  PubMed  Google Scholar 

  105. Kroon, E., Martinson, L. A., Kadoya, K., Bang, A. G., Kelly, O. G., Eliazer, S., Young, H., Richardson, M., Smart, N. G., Cunningham, J., Agulnick, A. D., D’Amour, K. A., Carpenter, M. K. & Baetge, E. E. 2008. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol, 26, 443–52.

    Article  PubMed  CAS  Google Scholar 

  106. Kuppan, P., Kelly, S., Polishevska, K., Hojanepesov, O., Seeberger, K., Korbutt, G. S. & Pepper, A. R. 2020. Co-localized immune protection using dexamethasone-eluting micelles in a murine islet allograft model. Am J Transplant, 20, 714–725.

    Article  PubMed  CAS  Google Scholar 

  107. Lablanche, S., Borot, S., Wojtusciszyn, A., Skaare, K., Penfornis, A., Malvezzi, P., Badet, L., Thivolet, C., Morelon, E., Buron, F., Renard, E., Tauveron, I., Villard, O., Munch, M., Sommacal, S., Clouaire, L., Jacquet, M., Gonsaud, L., Camillo-Brault, C., Colin, C., Bosson, J. L., Bosco, D., Berney, T., Kessler, L., Benhamou, P. Y. & Network, G. 2021. Ten-year outcomes of islet transplantation in patients with type 1 diabetes: Data from the Swiss-French GRAGIL network. Am J Transplant, 21, 3725–3733.

    Article  PubMed  CAS  Google Scholar 

  108. Lang, K. S., Georgiev, P., Recher, M., Navarini, A. A., Bergthaler, A., Heikenwalder, M., Harris, N. L., Junt, T., Odermatt, B., Clavien, P. A., Pircher, H., Akira, S., Hengartner, H. & Zinkernagel, R. M. 2006. Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling. J Clin Invest, 116, 2456–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Largiader, F., Kolb, E. & Binswanger, U. 1980. A long-term functioning human pancreatic islet allotransplant. Transplantation, 29, 76–7.

    Article  PubMed  CAS  Google Scholar 

  110. Lau, J., Jansson, L. & Carlsson, P. O. 2006. Islets transplanted intraportally into the liver are stimulated to insulin and glucagon release exclusively through the hepatic artery. Am J Transplant, 6, 967–75.

    Article  PubMed  CAS  Google Scholar 

  111. Lemos, J. R. N., Baidal, D. A., Poggioli, R., Fuenmayor, V., Chavez, C., Alvarez, A., Linetsky, E., Mauvais-Jarvis, F., Ricordi, C. & Alejandro, R. 2021. Prolonged islet allograft function is associated with female sex in patients after islet transplantation. J Clin Endocrinol Metab, 107, e973–e979.

    Article  PubMed Central  Google Scholar 

  112. Lemos, J. R. N., Baidal, D. A., Ricordi, C., Fuenmayor, V., Alvarez, A. & Alejandro, R. 2021. Survival After Islet Transplantation in Subjects With Type 1 Diabetes: Twenty-Year Follow-Up. Diabetes Care, 44, e67–e68.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Lois, N., Gardner, E., Mcfarland, M., Armstrong, D., Mcnally, C., Lavery, N. J., Campbell, C., Kirk, R. I., Bajorunas, D., Dunne, A., Cerami, A. & Brines, M. 2020. A Phase 2 Clinical Trial on the Use of Cibinetide for the Treatment of Diabetic Macular Edema. J Clin Med, 9.

    Google Scholar 

  114. Low, G., Hussein, N., Owen, R. J., Toso, C., Patel, V. H., Bhargava, R. & Shapiro, A. M. 2010. Role of imaging in clinical islet transplantation. Radiographics, 30, 353–66.

    Article  PubMed  Google Scholar 

  115. Ludwig, B., Ludwig, S., Steffen, A., Knauf, Y., Zimerman, B., Heinke, S., Lehmann, S., Schubert, U., Schmid, J., Bleyer, M., Schonmann, U., Colton, C. K., Bonifacio, E., Solimena, M., Reichel, A., Schally, A. V., Rotem, A., Barkai, U., Grinberg-Rashi, H., Kaup, F. J., Avni, Y., Jones, P. & Bornstein, S. R. 2017. Favorable outcome of experimental islet xenotransplantation without immunosuppression in a nonhuman primate model of diabetes. Proc Natl Acad Sci U S A, 114, 11745–11750.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Ludwig, B., Reichel, A., Steffen, A., Zimerman, B., Schally, A. V., Block, N. L., Colton, C. K., Ludwig, S., Kersting, S., Bonifacio, E., Solimena, M., Gendler, Z., Rotem, A., Barkai, U. & Bornstein, S. R. 2013. Transplantation of human islets without immunosuppression. Proc Natl Acad Sci U S A, 110, 19054–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Luzi, L., Hering, B. J., Socci, C., Raptis, G., Battezzati, A., Terruzzi, I., Falqui, L., Brandhorst, H., Brandhorst, D., Regalia, E., Brambilla, E., Secchi, A., Perseghin, G., Maffi, P., Bianchi, E., Mazzaferro, V., Gennari, L., Di Carlo, V., Federlin, K., Pozza, G. & Bretzel, R. G. 1996. Metabolic effects of successful intraportal islet transplantation in insulin-dependent diabetes mellitus. J Clin Invest, 97, 2611–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Maffi, P., Balzano, G., Ponzoni, M., Nano, R., Sordi, V., Melzi, R., Mercalli, A., Scavini, M., Esposito, A., Peccatori, J., Cantarelli, E., Messina, C., Bernardi, M., Del Maschio, A., Staudacher, C., Doglioni, C., Ciceri, F., Secchi, A. & Piemonti, L. 2013. Autologous pancreatic islet transplantation in human bone marrow. Diabetes, 62, 3523–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Maffi, P., Nano, R., Monti, P., Melzi, R., Sordi, V., Mercalli, A., Pellegrini, S., Ponzoni, M., Peccatori, J., Messina, C., Nocco, A., Cardillo, M., Scavini, M., Magistretti, P., Doglioni, C., Ciceri, F., Bloem, S. J., Roep, B. O., Secchi, A. & Piemonti, L. 2019. Islet Allotransplantation in the Bone Marrow of Patients With Type 1 Diabetes: A Pilot Randomized Trial. Transplantation, 103, 839–851.

    Article  PubMed  CAS  Google Scholar 

  120. Marfil-Garza, B. A., Hefler, J., Bermudez De Leon, M., Pawlick, R., Dadheech, N. & Shapiro, A. M. J. 2021. Progress in Translational Regulatory T Cell Therapies for Type 1 Diabetes and Islet Transplantation. Endocr Rev, 42, 198–218.

    Article  PubMed  Google Scholar 

  121. Marfil-Garza, B. A., Polishevska, K., Pepper, A. R. & Korbutt, G. S. 2020. Current State and Evidence of Cellular Encapsulation Strategies in Type 1 Diabetes. Compr Physiol, 10, 839–878.

    Article  PubMed  Google Scholar 

  122. Marfil-Garza, B. A., Imes, S., Verhoeff, K., Hefler, J., Lam, A., Dajani, K., Anderson, B., O’Gorman, D., Kin, T., Bigam, D., Senior, P. A., Shapiro, A. M. J. 2022. Pancreatic islet transplantation in type 1 diabetes: 20-year experience from a single-centre cohort in Canada. Lancet Diabetes Endocrinol, 10, 519–532.

    Article  PubMed  CAS  Google Scholar 

  123. Marfil-Garza, B. A., Shapiro, A. M. J. & Kin, T. 2021. Clinical Islet Transplantation: Current Progress and New Frontiers. J Hepatobiliary Pancreat Sci.

    Google Scholar 

  124. Martins, L. S. 2014. Autoimmune diabetes recurrence should be routinely monitored after pancreas transplantation. World J Transplant, 4, 183–7.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Meier, J. J., Hong-Mcatee, I., Galasso, R., Veldhuis, J. D., Moran, A., Hering, B. J. & Butler, P. C. 2006. Intrahepatic transplanted islets in humans secrete insulin in a coordinate pulsatile manner directly into the liver. Diabetes, 55, 2324–32.

    Article  PubMed  CAS  Google Scholar 

  126. Merani, S., Toso, C., Emamaullee, J. & Shapiro, A. M. 2008. Optimal implantation site for pancreatic islet transplantation. Br J Surg, 95, 1449–61.

    Article  PubMed  CAS  Google Scholar 

  127. Min, B. H., Shin, J. S., Kim, J. M., Kang, S. J., Kim, H. J., Yoon, I. H., Park, S. K., Choi, J. W., Lee, M. S. & Park, C. G. 2018. Delayed revascularization of islets after transplantation by IL-6 blockade in pig to non-human primate islet xenotransplantation model. Xenotransplantation, 25.

    Google Scholar 

  128. Mohan, J. F., Levisetti, M. G., Calderon, B., Herzog, J. W., Petzold, S. J. & Unanue, E. R. 2010. Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes. Nat Immunol, 11, 350–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Mojibian, M., Harder, B., Hurlburt, A., Bruin, J. E., Asadi, A. & Kieffer, T. J. 2013. Implanted islets in the anterior chamber of the eye are prone to autoimmune attack in a mouse model of diabetes. Diabetologia, 56, 2213–21.

    Article  PubMed  CAS  Google Scholar 

  130. Mosharmovahed, B., Fatahi, Y., Mohebbi, B., Ghorbanian, S. A. & Assadiasl, S. 2020. Tocilizumab in transplantation. Eur J Clin Pharmacol, 76, 765–773.

    Article  PubMed  CAS  Google Scholar 

  131. Müller, T. D., Finan, B., Clemmensen, C., Dimarchi, R. D. & Tschöp, M. H. 2017. The New Biology and Pharmacology of Glucagon. Physiol Rev, 97, 721–766.

    Article  PubMed  Google Scholar 

  132. Naziruddin, B., Iwahashi, S., Kanak, M. A., Takita, M., Itoh, T. & Levy, M. F. 2014. Evidence for instant blood-mediated inflammatory reaction in clinical autologous islet transplantation. Am J Transplant, 14, 428–37.

    Article  PubMed  CAS  Google Scholar 

  133. Noguchi, H., Miyagi-Shiohira, C., Nakashima, Y., Ebi, N., Hamada, E., Tamaki, Y., Kuwae, K., Kobayashi, N., Saitoh, I. & Watanabe, M. 2018. Modified cell-permeable JNK inhibitors efficiently prevents islet apoptosis and improves the outcome of islet transplantation. Sci Rep, 8, 11082.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Oh, S. H., Ward, C. L., Atala, A., Yoo, J. J. & Harrison, B. S. 2009. Oxygen generating scaffolds for enhancing engineered tissue survival. Biomaterials, 30, 757–62.

    Article  PubMed  CAS  Google Scholar 

  135. Park, K. S., Kim, Y. S., Kim, J. H., Choi, B., Kim, S. H., Tan, A. H., Lee, M. S., Lee, M. K., Kwon, C. H., Joh, J. W., Kim, S. J. & Kim, K. W. 2010. Trophic molecules derived from human mesenchymal stem cells enhance survival, function, and angiogenesis of isolated islets after transplantation. Transplantation, 89, 509–17.

    Article  PubMed  CAS  Google Scholar 

  136. Park, S. & Lee, D. 2017. The anterior chamber of the eye as a site for pancreatic islet transplantation. Journal of Industrial and Engineering Chemistry, 29–35.

    Google Scholar 

  137. Pattou, F., Kerr-Conte, J. & Wild, D. 2010. GLP-1-receptor scanning for imaging of human beta cells transplanted in muscle. N Engl J Med, 363, 1289–90.

    Article  PubMed  Google Scholar 

  138. Paty, B. W., Ryan, E. A., Shapiro, A. M., Lakey, J. R. & Robertson, R. P. 2002. Intrahepatic islet transplantation in type 1 diabetic patients does not restore hypoglycemic hormonal counterregulation or symptom recognition after insulin independence. Diabetes, 51, 3428–34.

    Article  PubMed  CAS  Google Scholar 

  139. Paul, P. K., Das, R., Drow, T. J., De Souza, A. H., Balamurugan, A. N., Belt Davis, D. & Galipeau, J. 2022. Pancreatic Stellate Cells Prolong Ex Vivo Islet Viability and Function and Improve Engraftment. Stem Cells Transl Med.

    Google Scholar 

  140. Pedraza, E., Coronel, M. M., Fraker, C. A., Ricordi, C. & Stabler, C. L. 2012. Preventing hypoxia-induced cell death in beta cells and islets via hydrolytically activated, oxygen-generating biomaterials. Proc Natl Acad Sci U S A, 109, 4245–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Pepper, A. R., Gala-Lopez, B., Pawlick, R., Merani, S., Kin, T. & Shapiro, A. M. 2015. A prevascularized subcutaneous device-less site for islet and cellular transplantation. Nat Biotechnol, 33, 518–23.

    Article  PubMed  CAS  Google Scholar 

  142. Pestana, N., Malheiro, J., Silva, F., Silva, A., Ribeiro, C., Pedroso, S., Almeida, M., Dias, L., Henriques, A. C. & Martins, S. 2020. Impact of Pancreatic Autoantibodies in Pancreas Graft Survival After Pancreas-Kidney Transplantation. Transplant Proc, 52, 1370–1375.

    Article  PubMed  CAS  Google Scholar 

  143. Petersdorf, E. W. 2004. HLA matching in allogeneic stem cell transplantation. Curr Opin Hematol, 11, 386–91.

    Article  PubMed  CAS  Google Scholar 

  144. Piemonti, L., Everly, M. J., Maffi, P., Scavini, M., Poli, F., Nano, R., Cardillo, M., Melzi, R., Mercalli, A., Sordi, V., Lampasona, V., Espadas De Arias, A., Scalamogna, M., Bosi, E., Bonifacio, E., Secchi, A. & Terasaki, P. I. 2013. Alloantibody and autoantibody monitoring predicts islet transplantation outcome in human type 1 diabetes. Diabetes, 62, 1656–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Pomposelli, T., Schuetz, C., Wang, P. & Yamada, K. 2021. A Strategy to Simultaneously Cure Type 1 Diabetes and Diabetic Nephropathy by Transplant of Composite Islet-Kidney Grafts. Front Endocrinol (Lausanne), 12, 632605.

    Article  PubMed  Google Scholar 

  146. Primavera, R., Razavi, M., Kevadiya, B. D., Wang, J., Vykunta, A., Di Mascolo, D., Decuzzi, P. & Thakor, A. S. 2021. Enhancing islet transplantation using a biocompatible collagen-PDMS bioscaffold enriched with dexamethasone-microplates. Biofabrication, 13.

    Google Scholar 

  147. Prochorov, A. V., Tretjak, S. I., Goranov, V. A., Glinnik, A. A. & Goltsev, M. V. 2008. Treatment of insulin dependent diabetes mellitus with intravascular transplantation of pancreatic islet cells without immunosuppressive therapy. Adv Med Sci, 53, 240–4.

    Article  PubMed  CAS  Google Scholar 

  148. Pugliese, A. 2017. Autoreactive T cells in type 1 diabetes. J Clin Invest, 127, 2881–2891.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Pugliese, A., Reijonen, H. K., Nepom, J. & Burke, G. W. 2011. Recurrence of autoimmunity in pancreas transplant patients: research update. Diabetes Manag (Lond), 1, 229–238.

    Article  PubMed  Google Scholar 

  150. Pyzdrowski, K. L., Kendall, D. M., Halter, J. B., Nakhleh, R. E., Sutherland, D. E. & Robertson, R. P. 1992. Preserved insulin secretion and insulin independence in recipients of islet autografts. N Engl J Med, 327, 220–6.

    Article  PubMed  CAS  Google Scholar 

  151. Qi, M., Lacik, I., Kollarikova, G., Strand, B. L., Formo, K., Wang, Y., Marchese, E., Mendoza-Elias, J. E., Kinzer, K. P., Gatti, F., Paushter, D., Patel, S. & Oberholzer, J. 2011. A recommended laparoscopic procedure for implantation of microcapsules in the peritoneal cavity of non-human primates. J Surg Res, 168, e117–23.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Rafael, E., Ryan, E. A., Paty, B. W., Oberholzer, J., Imes, S., Senior, P., Mcdonald, C., Lakey, J. R. & Shapiro, A. M. 2003. Changes in liver enzymes after clinical islet transplantation. Transplantation, 76, 1280–4.

    Article  PubMed  CAS  Google Scholar 

  153. Rafael, E., Tibell, A., Ryden, M., Lundgren, T., Savendahl, L., Borgstrom, B., Arnelo, U., Isaksson, B., Nilsson, B., Korsgren, O. & Permert, J. 2008. Intramuscular autotransplantation of pancreatic islets in a 7-year-old child: a 2-year follow-up. Am J Transplant, 8, 458–62.

    Article  PubMed  CAS  Google Scholar 

  154. Ramzy, A., Thompson, D. M., Ward-Hartstonge, K. A., Ivison, S., Cook, L., Garcia, R. V., Loyal, J., Kim, P. T. W., Warnock, G. L., Levings, M. K. & Kieffer, T. J. 2021. Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell, 28, 2047–2061 e5.

    Google Scholar 

  155. Rehfeld, J. F. 2018. The Origin and Understanding of the Incretin Concept. Front Endocrinol (Lausanne), 9, 387.

    Article  PubMed  Google Scholar 

  156. Rezania, A., Bruin, J. E., Arora, P., Rubin, A., Batushansky, I., Asadi, A., O’Dwyer, S., Quiskamp, N., Mojibian, M., Albrecht, T., Yang, Y. H., Johnson, J. D. & Kieffer, T. J. 2014. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol, 32, 1121–33.

    Article  PubMed  CAS  Google Scholar 

  157. Rickels, M. R. 2012. Recovery of endocrine function after islet and pancreas transplantation. Curr Diab Rep, 12, 587–96.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Rickels, M. R., Fuller, C., Dalton-Bakes, C., Markmann, E., Palanjian, M., Cullison, K., Tiao, J., Kapoor, S., Liu, C., Naji, A. & Teff, K. L. 2015. Restoration of Glucose Counterregulation by Islet Transplantation in Long-standing Type 1 Diabetes. Diabetes, 64, 1713–8.

    Article  PubMed  CAS  Google Scholar 

  159. Rickels, M. R., Liu, C., Shlansky-Goldberg, R. D., Soleimanpour, S. A., Vivek, K., Kamoun, M., Min, Z., Markmann, E., Palangian, M., Dalton-Bakes, C., Fuller, C., Chiou, A. J., Barker, C. F., Luning Prak, E. T. & Naji, A. 2013. Improvement in beta-cell secretory capacity after human islet transplantation according to the CIT07 protocol. Diabetes, 62, 2890–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Rickels, M. R., Mueller, R., Markmann, J. F. & Naji, A. 2009. Effect of glucagon-like peptide-1 on beta- and alpha-cell function in isolated islet and whole pancreas transplant recipients. J Clin Endocrinol Metab, 94, 181–9.

    Article  PubMed  CAS  Google Scholar 

  161. Rickels, M. R., Mueller, R., Teff, K. L. & Naji, A. 2010. beta-Cell secretory capacity and demand in recipients of islet, pancreas, and kidney transplants. J Clin Endocrinol Metab, 95, 1238–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Rickels, M. R. & Robertson, R. P. 2019. Pancreatic Islet Transplantation in Humans: Recent Progress and Future Directions. Endocr Rev, 40, 631–668.

    Article  PubMed  Google Scholar 

  163. Rickels, M. R., Schutta, M. H., Mueller, R., Kapoor, S., Markmann, J. F., Naji, A. & Teff, K. L. 2007. Glycemic thresholds for activation of counterregulatory hormone and symptom responses in islet transplant recipients. J Clin Endocrinol Metab, 92, 873–9.

    Article  PubMed  CAS  Google Scholar 

  164. Ricordi, C., Naji, A., Rickels, M. R., Bruinsma, B., Marigowda, G., Ross, L., Wang, C., Pagliuca, F. W., Sanna, B., Kean, L. S., Peters, A., Witkowski, P. & Markmann, J. F. 2022. Stem cell-derived, fully differentiated islet cells for type 1 diabetes. 58th European Association for the Study of Diabetes Meeting. Stockholm, Sweden.

    Google Scholar 

  165. Robert, J. J., Chauvet, D., Darmaun, D. & Leblanc, H. 1993. Hepatic glucose production during intraperitoneal and intravenous closed-loop insulin regulation of blood glucose in type 1 (insulin-dependent) diabetic patients. Diabetologia, 36, 1185–90.

    Article  PubMed  CAS  Google Scholar 

  166. Robertson, R. P. 2007. Estimation of beta-cell mass by metabolic tests: necessary, but how sufficient? Diabetes, 56, 2420–4.

    Article  PubMed  CAS  Google Scholar 

  167. Robertson, R. P., Bogachus, L. D., Oseid, E., Parazzoli, S., Patti, M. E., Rickels, M. R., Schuetz, C., Dunn, T., Pruett, T., Balamurugan, A. N., Sutherland, D. E., Beilman, G. & Bellin, M. D. 2015. Assessment of beta-cell mass and alpha- and beta-cell survival and function by arginine stimulation in human autologous islet recipients. Diabetes, 64, 565–72.

    Article  PubMed  CAS  Google Scholar 

  168. Robertson, R. P., Sutherland, D. E. & Lanz, K. J. 1999. Normoglycemia and preserved insulin secretory reserve in diabetic patients 10-18 years after pancreas transplantation. Diabetes, 48, 1737–40.

    Article  PubMed  CAS  Google Scholar 

  169. Roep, B. O. 2008. Islet autoreactive CD8 T-cells in type 1 diabetes: licensed to kill? Diabetes, 57, 1156.

    Article  PubMed  CAS  Google Scholar 

  170. Roep, B. O., Stobbe, I., Duinkerken, G., Van Rood, J. J., Lernmark, A., Keymeulen, B., Pipeleers, D., Claas, F. H. & De Vries, R. R. 1999. Auto- and alloimmune reactivity to human islet allografts transplanted into type 1 diabetic patients. Diabetes, 48, 484–90.

    Article  PubMed  CAS  Google Scholar 

  171. Rong, Z., Wang, M., Hu, Z., Stradner, M., Zhu, S., Kong, H., Yi, H., Goldrath, A., Yang, Y. G., Xu, Y. & Fu, X. 2014. An effective approach to prevent immune rejection of human ESC-derived allografts. Cell Stem Cell, 14, 121–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Rorsman, P. & Ashcroft, F. M. 2018. Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men. Physiol Rev, 98, 117–214.

    Article  PubMed  CAS  Google Scholar 

  173. Ryan, E. A., Lakey, J. R., Paty, B. W., Imes, S., Korbutt, G. S., Kneteman, N. M., Bigam, D., Rajotte, R. V. & Shapiro, A. M. 2002. Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes, 51, 2148–57.

    Article  PubMed  CAS  Google Scholar 

  174. Sahraoui, A., Kloster-Jensen, K., Ueland, T., Korsgren, O., Foss, A. & Scholz, H. 2014. Anakinra and tocilizumab enhance survival and function of human islets during culture: implications for clinical islet transplantation. Cell Transplant, 23, 1199–211.

    Article  PubMed  Google Scholar 

  175. Sakata, N., Tan, A., Chan, N., Obenaus, A., Mace, J., Peverini, R., Sowers, L., Chinnock, R. & Hathout, E. 2009. Efficacy comparison between intraportal and subcapsular islet transplants in a murine diabetic model. Transplant Proc, 41, 346–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Salehi, A., Dornonville De La Cour, C., Håkanson, R. & Lundquist, I. 2004. Effects of ghrelin on insulin and glucagon secretion: a study of isolated pancreatic islets and intact mice. Regul Pept, 118, 143–50.

    Article  PubMed  CAS  Google Scholar 

  177. Sanchez-Rangel, E., Deajon-Jackson, J. & Hwang, J. J. 2022. Pathophysiology and management of hypoglycemia in diabetes. Ann N Y Acad Sci.

    Google Scholar 

  178. Saudek, F., Hladikova, Z., Hagerf, B., Nemetova, L., Girman, P., Kriz, J., Marada, T., Habart, D., Berkova, Z., Leontovyc, I. & Fronek, J. 2022. Transplantation of Pancreatic Islets Into the Omentum Using a Biocompatible Plasma-Thrombin Gel: First Experience at the Institute for Clinical and Experimental Medicine in Prague. Transplant Proc, 54, 806–810.

    Article  PubMed  CAS  Google Scholar 

  179. Sawitzki, B., Harden, P. N., Reinke, P., Moreau, A., Hutchinson, J. A., Game, D. S., Tang, Q., Guinan, E. C., Battaglia, M., Burlingham, W. J., Roberts, I. S. D., Streitz, M., Josien, R., Boger, C. A., Scotta, C., Markmann, J. F., Hester, J. L., Juerchott, K., Braudeau, C., James, B., Contreras-Ruiz, L., Van Der Net, J. B., Bergler, T., Caldara, R., Petchey, W., Edinger, M., Dupas, N., Kapinsky, M., Mutzbauer, I., Otto, N. M., Ollinger, R., Hernandez-Fuentes, M. P., Issa, F., Ahrens, N., Meyenberg, C., Karitzky, S., Kunzendorf, U., Knechtle, S. J., Grinyo, J., Morris, P. J., Brent, L., Bushell, A., Turka, L. A., Bluestone, J. A., Lechler, R. I., Schlitt, H. J., Cuturi, M. C., Schlickeiser, S., Friend, P. J., Miloud, T., Scheffold, A., Secchi, A., Crisalli, K., Kang, S. M., Hilton, R., Banas, B., Blancho, G., Volk, H. D., Lombardi, G., Wood, K. J. & Geissler, E. K. 2020. Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials. Lancet, 395, 1627–1639.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Saxena, V., Ondr, J. K., Magnusen, A. F., Munn, D. H. & Katz, J. D. 2007. The countervailing actions of myeloid and plasmacytoid dendritic cells control autoimmune diabetes in the nonobese diabetic mouse. J Immunol, 179, 5041–53.

    Article  PubMed  CAS  Google Scholar 

  181. Seino, S. & Shibasaki, T. 2005. PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol Rev, 85, 1303–42.

    Article  PubMed  CAS  Google Scholar 

  182. Shapiro, A. M., Lakey, J. R., Ryan, E. A., Korbutt, G. S., Toth, E., Warnock, G. L., Kneteman, N. M. & Rajotte, R. V. 2000. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med, 343, 230–8.

    Article  PubMed  CAS  Google Scholar 

  183. Shapiro, A. M. J. 2007. A Historical Perspective on Experimental and Clinical Islet Transplantation. In: Shapiro, A. M. J. & Shaw, A. M. (eds.) Islet Transplantation and Beta-cell Replacement Therapy. 1st edition ed. New York, NY: Informa Healthcare.

    Chapter  Google Scholar 

  184. Shapiro, A. M. J., Gallant, H. L., Hao, E. G., Lakey, J. R., Mccready, T., Rajotte, R. V., Yatscoff, R. W. & Kneteman, N. M. 2005. The portal immunosuppressive storm: relevance to islet transplantation? Ther Drug Monit, 27, 35–7.

    Article  PubMed  Google Scholar 

  185. Shapiro, A. M. J., Lakey, J. R., Rajotte, R. V., Warnock, G. L., Friedlich, M. S., Jewell, L. D. & Kneteman, N. M. 1995. Portal vein thrombosis after transplantation of partially purified pancreatic islets in a combined human liver/islet allograft. Transplantation, 59, 1060–3.

    Article  PubMed  CAS  Google Scholar 

  186. Shapiro, A. M. J., Thompson, D., Donner, T. W., Bellin, M. D., Hsueh, W., Pettus, J., Wilensky, J., Daniels, M., Wang, R. M., Brandon, E. P., Jaiman, M. S., Kroon, E. J., D’Amour, K. A. & Foyt, H. L. 2021. Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell Rep Med, 2, 100466.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Sibley, R. K. & Sutherland, D. E. 1987. Pancreas transplantation. An immunohistologic and histopathologic examination of 100 grafts. Am J Pathol, 128, 151–70.

    PubMed  PubMed Central  CAS  Google Scholar 

  188. Smood, B., Bottino, R., Hara, H. & Cooper, D. K. C. 2019. Is the renal subcapsular space the preferred site for clinical porcine islet xenotransplantation? Review article. Int J Surg, 69, 100–107.

    Article  PubMed  PubMed Central  Google Scholar 

  189. Solass, W., Horvath, P., Struller, F., Konigsrainer, I., Beckert, S., Konigsrainer, A., Weinreich, F. J. & Schenk, M. 2016. Functional vascular anatomy of the peritoneum in health and disease. Pleura Peritoneum, 1, 145–158.

    Article  PubMed  PubMed Central  Google Scholar 

  190. Soon-Shiong, P., Heintz, R. E., Merideth, N., Yao, Q. X., Yao, Z., Zheng, T., Murphy, M., Moloney, M. K., Schmehl, M., Harris, M., et al. 1994. Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation. Lancet, 343, 950–1.

    Article  PubMed  CAS  Google Scholar 

  191. Speier, S., Nyqvist, D., Cabrera, O., Yu, J., Molano, R. D., Pileggi, A., Moede, T., Kohler, M., Wilbertz, J., Leibiger, B., Ricordi, C., Leibiger, I. B., Caicedo, A. & Berggren, P. O. 2008. Noninvasive in vivo imaging of pancreatic islet cell biology. Nat Med, 14, 574–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Stegall, M. D., Lafferty, K. J., Kam, I. & Gill, R. G. 1996. Evidence of recurrent autoimmunity in human allogeneic islet transplantation. Transplantation, 61, 1272–4.

    Article  PubMed  CAS  Google Scholar 

  193. Sutherland, D. E., Sibley, R., Xu, X. Z., Michael, A., Srikanta, A. M., Taub, F., Najarian, J. & Goetz, F. C. 1984. Twin-to-twin pancreas transplantation: reversal and reenactment of the pathogenesis of type I diabetes. Trans Assoc Am Physicians, 97, 80–7.

    PubMed  CAS  Google Scholar 

  194. Szempruch, K. R., Banerjee, O., Mccall, R. C. & Desai, C. S. 2019. Use of anti-inflammatory agents in clinical islet cell transplants: A qualitative systematic analysis. Islets, 11, 65–75.

    Article  PubMed  PubMed Central  Google Scholar 

  195. Takemoto, N., Liu, X., Takii, K., Teramura, Y. & Iwata, H. 2014. Transplantation of co-aggregates of Sertoli cells and islet cells into liver without immunosuppression. Transplantation, 97, 287–93.

    Article  PubMed  CAS  Google Scholar 

  196. Teuscher, A. U., Kendall, D. M., Smets, Y. F., Leone, J. P., Sutherland, D. E. & Robertson, R. P. 1998. Successful islet autotransplantation in humans: functional insulin secretory reserve as an estimate of surviving islet cell mass. Diabetes, 47, 324–30.

    Article  PubMed  CAS  Google Scholar 

  197. Todo, S., Yamashita, K., Goto, R., Zaitsu, M., Nagatsu, A., Oura, T., Watanabe, M., Aoyagi, T., Suzuki, T., Shimamura, T., Kamiyama, T., Sato, N., Sugita, J., Hatanaka, K., Bashuda, H., Habu, S., Demetris, A. J. & Okumura, K. 2016. A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology, 64, 632–43.

    Article  PubMed  CAS  Google Scholar 

  198. Valdes-Gonzalez, R. A., Dorantes, L. M., Garibay, G. N., Bracho-Blanchet, E., Mendez, A. J., Davila-Perez, R., Elliott, R. B., Teran, L. & White, D. J. 2005. Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study. Eur J Endocrinol, 153, 419–27.

    Article  PubMed  CAS  Google Scholar 

  199. Van Hulle, F., De Groot, K., Hilbrands, R., Van De Velde, U., Suenens, K., Stange, G., De Mesmaeker, I., De Paep, D. L., Ling, Z., Roep, B., Gillard, P., Pipeleers, D., Keymeulen, B. & Jacobs-Tulleneers-Thevissen, D. 2022. Function and composition of pancreatic islet cell implants in omentum of type 1 diabetes patients. Am J Transplant, 22, 927–936.

    Article  PubMed  Google Scholar 

  200. Vantyghem, M.-C., Chetboun, M., Gmyr, V., Jannin, A., Espiard, S., Le Mapihan, K., Raverdy, V., Delalleau, N., Machuron, F., Hubert, T., Frimat, M., Van Belle, E., Hazzan, M., Pigny, P., Noel, C., Caiazzo, R., Kerr-Conte, J. & Pattou, F. 2019. Ten-Year Outcome of Islet Alone or Islet After Kidney Transplantation in Type 1 Diabetes: A Prospective Parallel-Arm Cohort Study. Diabetes Care, dc190401.

    Google Scholar 

  201. Vantyghem, M. C., Chetboun, M., Gmyr, V., Jannin, A., Espiard, S., Le Mapihan, K., Raverdy, V., Delalleau, N., Machuron, F., Hubert, T., Frimat, M., Van Belle, E., Hazzan, M., Pigny, P., Noel, C., Caiazzo, R., Kerr-Conte, J. & Pattou, F. 2019. Ten-Year Outcome of Islet Alone or Islet After Kidney Transplantation in Type 1 Diabetes: A Prospective Parallel-Arm Cohort Study. Diabetes Care, 42, 2042–2049.

    Article  PubMed  Google Scholar 

  202. Vantyghem, M. C., Marcelli-Tourvieille, S., Fermon, C., Duhamel, A., Raverdy, V., Arnalsteen, L., Kerr-Conte, J., Noel, C., Fontaine, P. & Pattou, F. 2009. Intraperitoneal insulin infusion versus islet transplantation: comparative study in patients with type 1 diabetes. Transplantation, 87, 66–71.

    Article  PubMed  CAS  Google Scholar 

  203. Vegas, A. J., Veiseh, O., Gurtler, M., Millman, J. R., Pagliuca, F. W., Bader, A. R., Doloff, J. C., Li, J., Chen, M., Olejnik, K., Tam, H. H., Jhunjhunwala, S., Langan, E., Aresta-Dasilva, S., Gandham, S., Mcgarrigle, J. J., Bochenek, M. A., Hollister-Lock, J., Oberholzer, J., Greiner, D. L., Weir, G. C., Melton, D. A., Langer, R. & Anderson, D. G. 2016. Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med, 22, 306–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Vendrame, F., Hopfner, Y. Y., Diamantopoulos, S., Virdi, S. K., Allende, G., Snowhite, I. V., Reijonen, H. K., Chen, L., Ruiz, P., Ciancio, G., Hutton, J. C., Messinger, S., Burke, G. W. & Pugliese, A. 2016. Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas-Kidney Transplants. Am J Transplant, 16, 235–45.

    Article  PubMed  CAS  Google Scholar 

  205. Vendrame, F., Pileggi, A., Laughlin, E., Allende, G., Martin-Pagola, A., Molano, R. D., Diamantopoulos, S., Standifer, N., Geubtner, K., Falk, B. A., Ichii, H., Takahashi, H., Snowhite, I., Chen, Z., Mendez, A., Chen, L., Sageshima, J., Ruiz, P., Ciancio, G., Ricordi, C., Reijonen, H., Nepom, G. T., Burke, G. W. & Pugliese, A. 2010. Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells. Diabetes, 59, 947–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  206. Vénéreau, E., Ceriotti, C. & Bianchi, M. E. 2015. DAMPs from Cell Death to New Life. Front Immunol, 6, 422.

    Article  PubMed  PubMed Central  Google Scholar 

  207. Venturini, M., Maffi, P., Querques, G., Agostini, G., Piemonti, L., Sironi, S., De Cobelli, F., Fiorina, P., Secchi, A. & Del Maschio, A. 2015. Hepatic steatosis after islet transplantation: Can ultrasound predict the clinical outcome? A longitudinal study in 108 patients. Pharmacol Res, 98, 52–9.

    Article  PubMed  Google Scholar 

  208. Verhoeff, K., Marfil-Garza, B. A., Dajani, K., Bigam, D. L., Anderson, B., Kin, T., Lam, A., O’Gorman, D., Senior, P. A. & Shapiro, A. M. J. 2022. C-peptide Targets and Patient-centered Outcomes of Relevance to Cellular Transplantation for Diabetes. Transplantation.

    Google Scholar 

  209. Verhoeff, K., Marfil-Garza, B. A., Sandha, G., Cooper, D., Dajani, K., Bigam, D. L., Anderson, B., Kin, T., Lam, A., O’Gorman, D., Senior, P. A., Ricordi, C. & Shapiro, A. M. J. 2022. Outcomes Following Extrahepatic and Intraportal Pancreatic Islet Transplantation: A Comparative Cohort Study. Transplantation, 106, 2224–2231.

    Article  PubMed  CAS  Google Scholar 

  210. Vethakkan, S. R., Walters, J. M., Gooley, J. L., Boston, R. C., Kay, T. W., Goodman, D. J., Jenkins, A. J. & Ward, G. M. 2014. The incretin response after successful islet transplantation. Transplantation, 97, e9–11.

    Article  PubMed  Google Scholar 

  211. Villiger, P., Ryan, E. A., Owen, R., O’Kelly, K., Oberholzer, J., Al Saif, F., Kin, T., Wang, H., Larsen, I., Blitz, S. L., Menon, V., Senior, P., Bigam, D. L., Paty, B., Kneteman, N. M., Lakey, J. R. & Shapiro, A. M. 2005. Prevention of bleeding after islet transplantation: lessons learned from a multivariate analysis of 132 cases at a single institution. Am J Transplant, 5, 2992–8.

    Article  PubMed  CAS  Google Scholar 

  212. Vlahos, A. E. & Sefton, M. V. 2018. Muted fibrosis from protected islets. Nat Biomed Eng, 2, 791–792.

    Article  PubMed  Google Scholar 

  213. Walker, J. T., Saunders, D. C., Brissova, M. & Powers, A. C. 2021. The Human Islet: Mini-Organ With Mega-Impact. Endocr Rev, 42, 605–657.

    Article  PubMed  PubMed Central  Google Scholar 

  214. Wang, C., Du, X., He, S., Yuan, Y., Han, P., Wang, D., Chen, Y., Liu, J., Tian, B., Yang, G., Yi, S., Gao, F., Zhong, Z., Li, H., Cheng, J. & Lu, Y. 2017. A preclinical evaluation of alternative site for islet allotransplantation. PLoS One, 12, e0174505.

    Article  PubMed  PubMed Central  Google Scholar 

  215. Wang, L. H., Ernst, A. U., Flanders, J. A., Liu, W., Wang, X., Datta, A. K., Epel, B., Kotecha, M., Papas, K. K. & Ma, M. 2021. An inverse-breathing encapsulation system for cell delivery. Sci Adv, 7.

    Google Scholar 

  216. Ward, C., Faleo, G., Duh, Q., Hebrok, M., Chang, W., Stock, P. & Tang, Q. 2018. Reversal of Diabetes and Preservation of Pancreatic Islet Grafts in the Extrahepatic Space with Novel Parathyroid Gland Co-Transplantation. Transplantation, 102, S368–S369.

    Article  Google Scholar 

  217. Wassmer, C. H., Lebreton, F., Bellofatto, K., Perez, L., Cottet-Dumoulin, D., Andres, A., Bosco, D., Berney, T., Othenin-Girard, V., Martinez De Tejada, B., Cohen, M., Olgasi, C., Follenzi, A., Berishvili, E. & Consortium, V. 2021. Bio-Engineering of Pre-Vascularized Islet Organoids for the Treatment of Type 1 Diabetes. Transpl Int, 35, 10214.

    Article  PubMed  Google Scholar 

  218. White, S. A., London, N. J., Johnson, P. R., Davies, J. E., Pollard, C., Contractor, H. H., Hughes, D. P., Robertson, G. S., Musto, P. P. & Dennison, A. R. 2000. The risks of total pancreatectomy and splenic islet autotransplantation. Cell Transplant, 9, 19–24.

    Article  PubMed  CAS  Google Scholar 

  219. Witkowski, P., Odorico, J., Pyda, J., Anteby, R., Stratta, R. J., Schrope, B. A., Hardy, M. A., Buse, J., Leventhal, J. R., Cui, W., Hussein, S., Niederhaus, S., Gaglia, J., Desai, C. S., Wijkstrom, M., Kandeel, F., Bachul, P. J., Becker, Y. T., Wang, L. J., Robertson, R. P., Olaitan, O. K., Kozlowski, T., Abrams, P. L., Josephson, M. A., Andreoni, K. A., Harland, R. C., Kandaswamy, R., Posselt, A. M., Szot, G. L., Ricordi, C. & On Behalf of the Islets for US, C. 2021. Arguments against the Requirement of a Biological License Application for Human Pancreatic Islets: The Position Statement of the Islets for US Collaborative Presented during the FDA Advisory Committee Meeting. J Clin Med, 10.

    Google Scholar 

  220. Wszola, M., Berman, A., Gorski, L., Ostaszewska, A., Serwanska-Swietek, M., Krajewska, M., Lipinska, A., Chmura, A. & Kwiatkowski, A. 2018. Endoscopic Islet Autotransplantation Into Gastric Submucosa-1000-Day Follow-up of Patients. Transplant Proc, 50, 2119–2123.

    Article  PubMed  CAS  Google Scholar 

  221. Yamane, K., Anazawa, T., Tada, S., Fujimoto, N., Inoguchi, K., Emoto, N., Nagai, K., Masui, T., Okajima, H., Takaori, K., Sumi, S. & Uemoto, S. 2020. Mitomycin C treatment improves pancreatic islet graft longevity in intraportal islet transplantation by suppressing proinflammatory response. Sci Rep, 10, 12086.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  222. Yao, M., Domogatskaya, A., Agren, N., Watanabe, M., Tokodai, K., Brines, M., Cerami, A., Ericzon, B. G., Kumagai-Braesch, M. & Lundgren, T. 2021. Cibinetide Protects Isolated Human Islets in a Stressful Environment and Improves Engraftment in the Perspective of Intra Portal Islet Transplantation. Cell Transplant, 30, 9636897211039739.

    Article  PubMed  Google Scholar 

  223. Yoshihara, E., O’Connor, C., Gasser, E., Wei, Z., Oh, T. G., Tseng, T. W., Wang, D., Cayabyab, F., Dai, Y., Yu, R. T., Liddle, C., Atkins, A. R., Downes, M. & Evans, R. M. 2020. Immune-evasive human islet-like organoids ameliorate diabetes. Nature, 586, 606–611.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  224. Yoshimatsu, G., Sakata, N., Tsuchiya, H., Minowa, T., Takemura, T., Morita, H., Hata, T., Fukase, M., Aoki, T., Ishida, M., Motoi, F., Naitoh, T., Katayose, Y., Egawa, S. & Unno, M. 2015. The co-transplantation of bone marrow derived mesenchymal stem cells reduced inflammation in intramuscular islet transplantation. PLoS One, 10, e0117561.

    Article  PubMed  PubMed Central  Google Scholar 

  225. Zhang, Q. & Reed, E. F. 2016. The importance of non-HLA antibodies in transplantation. Nat Rev Nephrol, 12, 484–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

Braulio A. Marfil–Garza was supported by a scholarship from the Alberta Transplant Institute and is currently the Director of Pancreatic Islet Transplantation at TecSalud - Tecnologico de Monterrey. Nerea Cuesta-Gomez is currently supported by the Natural Sciences and Engineering Research Council – Collaborative Research and Training Experience (NSERC-CREATE) program and Juvenile Diabetes Research Foundation Canada. AM James Shapiro is supported through a Canada Research Chair (Tier 1) in Regenerative Medicine and Transplant Surgery, and through grant support from the Juvenile Diabetes Research Foundation, Diabetes Canada, The Canadian Donation and Transplant Research Project, the Diabetes Research Institute Foundation of Canada, the Alberta Diabetes Foundation, and the Canadian Stem Cell Network.

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Authors and Affiliations

  1. Alberta Diabetes Institute, Edmonton, AB, Canada

    Braulio A. Marfil-Garza, Nerea Cuesta-Gomez & A. M. James Shapiro

  2. Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada

    Braulio A. Marfil-Garza & A. M. James Shapiro

  3. Tecnologico de Monterrey, Institute for Obesity Research, Hospital Zambrano Hellion, TecSalud, San Pedro Garza Garcia, Mexico

    Braulio A. Marfil-Garza

  4. Department of Surgery, University of Alberta, Edmonton, AB, Canada

    Nerea Cuesta-Gomez & A. M. James Shapiro

Authors
  1. Braulio A. Marfil-Garza
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  2. Nerea Cuesta-Gomez
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  3. A. M. James Shapiro
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Corresponding author

Correspondence to A. M. James Shapiro .

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Editors and Affiliations

  1. Diabetes Research Institute and Clinical Unit of Regenerative Medicine and Transplant, IRCCS San Raffaele Hospital/Vita-Salute San Raffaele University, Milan, Italy

    Lorenzo Piemonti

  2. Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Jon Odorico

  3. University of British Columbia, Vancouver, BC, Canada

    Timothy J . Kieffer

  4. IRCCS Ospedale San Raffaele, Diabetes Research Institute, Milan, Italy

    Valeria Sordi

  5. Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands

    Eelco de Koning

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Marfil-Garza, B.A., Cuesta-Gomez, N., Shapiro, A.M.J. (2023). Considerations Pertaining to Implant Sites for Cell-Based Insulin Replacement Therapies. In: Piemonti, L., Odorico, J., Kieffer, T.J..., Sordi, V., de Koning, E. (eds) Pluripotent Stem Cell Therapy for Diabetes. Springer, Cham. https://doi.org/10.1007/978-3-031-41943-0_16

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  • DOI: https://doi.org/10.1007/978-3-031-41943-0_16

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  • Online ISBN: 978-3-031-41943-0

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