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Wong JM, Pepper AR. Status of islet transplantation and innovations to sustainable outcomes: novel sites, cell sources, and drug delivery strategies. FRONTIERS IN TRANSPLANTATION 2024; 3:1485444. [PMID: 39553396 PMCID: PMC11565603 DOI: 10.3389/frtra.2024.1485444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 10/21/2024] [Indexed: 11/19/2024]
Abstract
Islet transplantation (ITx) is an effective means to restore physiologic glycemic regulation in those living with type 1 diabetes; however, there are a handful of barriers that prevent the broad application of this functionally curative procedure. The restricted cell supply, requisite for life-long toxic immunosuppression, and significant immediate and gradual graft attrition limits the procedure to only those living with brittle diabetes. While intraportal ITx is the primary clinical site, portal vein-specific factors including low oxygen tension and the instant blood-mediated inflammatory reaction are detrimental to initial engraftment and long-term function. These factors among others prevent the procedure from granting recipients long-term insulin independence. Herein, we provide an overview of the status and limitations of ITx, and novel innovations that address the shortcomings presented. Despite the marked progress highlighted in the review from as early as the initial islet tissue transplantation in 1893, ongoing efforts to improve the procedure efficacy and success are also explored. Progress in identifying unlimited cell sources, more favourable transplant sites, and novel drug delivery strategies all work to broaden ITx application and reduce adverse outcomes. Exploring combination of these approaches may uncover synergies that can further advance the field of ITx in providing sustainable functional cures. Finally, the potential of biomaterial strategies to facilitate immune evasion and local immune modulation are featured and may underpin successful application in alternative transplant sites.
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Affiliation(s)
| | - Andrew R. Pepper
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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Perez-Basterrechea M, Esteban MM, Vega JA, Obaya AJ. Tissue-engineering approaches in pancreatic islet transplantation. Biotechnol Bioeng 2018; 115:3009-3029. [PMID: 30144310 DOI: 10.1002/bit.26821] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/08/2018] [Accepted: 08/14/2018] [Indexed: 12/15/2022]
Abstract
Pancreatic islet transplantation is a promising alternative to whole-pancreas transplantation as a treatment of type 1 diabetes mellitus. This technique has been extensively developed during the past few years, with the main purpose of minimizing the complications arising from the standard protocols used in organ transplantation. By using a variety of strategies used in tissue engineering and regenerative medicine, pancreatic islets have been successfully introduced in host patients with different outcomes in terms of islet survival and functionality, as well as the desired normoglycemic control. Here, we describe and discuss those strategies to transplant islets together with different scaffolds, in combination with various cell types and diffusible factors, and always with the aim of reducing host immune response and achieving islet survival, regardless of the site of transplantation.
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Affiliation(s)
- Marcos Perez-Basterrechea
- Unidad de Terapia Celular y Medicina Regenerativa, Servicio de Hematología y Hemoterapia, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.,Plataforma de Terapias Avanzadas, Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Manuel M Esteban
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
| | - Jose A Vega
- Departamento de Morfología y Biología Celular, Universidad de Oviedo, Oviedo, Spain.,Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Alvaro J Obaya
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
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Gebe JA, Preisinger A, Gooden MD, D'Amico LA, Vernon RB. Local, Controlled Release In Vivo of Vascular Endothelial Growth Factor Within a Subcutaneous Scaffolded Islet Implant Reduces Early Islet Necrosis and Improves Performance of the Graft. Cell Transplant 2018; 27:531-541. [PMID: 29756517 PMCID: PMC6038045 DOI: 10.1177/0963689718754562] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Islet transplantation remains the only alternative to daily insulin therapy for control of type 1 diabetes (T1D) in humans. To avoid the drawbacks of intrahepatic islet transplantation, we are developing a scaffolded islet implant to transplant islets into nonhepatic sites. The implant test bed, sized for mice, consists of a limited (2-mm) thickness, large-pore polymeric sponge scaffold perforated with peripheral cavities that contain islets suspended in a collagen hydrogel. A central cavity in the scaffold holds a 2-mm diameter alginate sphere for controlled release of the angiogenic cytokine vascular endothelial growth factor ( VEGF). Host microvessels readily penetrate the scaffold and collagen gel to vascularize the islets. Here, we evaluate the performance of the implant in a subcutaneous (SC) graft site. Implants incorporating 500 syngeneic islets reversed streptozotocin-induced diabetes in mice approximately 30 d after SC placement. Controlled release of a modest quantity (20 ng) of VEGF within the implant significantly reduced the time to normoglycemia compared to control implants lacking VEGF. Investigation of underlying causes for this effect revealed that inclusion of 20 ng of VEGF in the implants significantly reduced central necrosis of islets 24 h after grafting and increased implant vascularization (measured 12 d after grafting). Collectively, our results demonstrate (1) that the scaffolded islet implant design can reverse diabetes in SC sites in the absence of prevascularization of the graft site and (2) that relatively low quantities of VEGF, delivered by controlled release within the implant, can be a useful approach to limit islet stress after grafting.
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Affiliation(s)
- John A Gebe
- 1 Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Anton Preisinger
- 1 Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Michel D Gooden
- 1 Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Leonard A D'Amico
- 1 Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.,2 Cancer Immunotherapy Trials, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Robert B Vernon
- 1 Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
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Transplant Site Influences the Immune Response After Islet Transplantation: Bone Marrow Versus Liver. Transplantation 2017; 101:1046-1055. [PMID: 27575689 DOI: 10.1097/tp.0000000000001462] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND The aim of this study was to characterize the immune response against intrabone marrow (BM-Tx) or intraliver (liver-Tx) transplanted islets in the presence or in the absence of immunosuppression. METHODS Less (C57BL/6 in Balb/c) and highly (Balb/c in C57BL/6) stringent major histocompatibility complex fully mismatched mouse models were used to evaluate the alloimmune response. Single antigen-mismatched mouse model (C57BL/6 RIP-GP in C57BL/6) was used to evaluate the antigen-specific immune response. Mice received tacrolimus (FK-506, 0.1 mg/kg per day)/mycophenolate mofetil (MMF, 60 mg/kg per day), and anti-CD3 (50 μg/day) either alone or in combination. RESULTS Transplant site did not impact the timing nor the kinetics of the alloimmune and single antigen-specific memory T cell responses in the absence of immunosuppression or in the presence of MMF/FK-506 combination. On the other hand, the median time to graft rejection was 28 ± 5.2 days and 16 ± 2.6 days (P = 0.14) in the presence of anti-CD3 treatment, 50 ± 12.5 days and 10 ± 1.3 days (P = 0.003) in the presence of anti-CD3/MMF/FK-506 treatment for liver-Tx and BM-Tx, respectively. Anti-CD3 did not differentially reach BM and liver tissues but was more effective in reducing graft associated T cell responses in liver-Tx than in BM-Tx. CONCLUSIONS Islets infused in the BM appear less protected from the adaptive immune response in the presence of the anti-CD3 treatment. This result raises some concerns over the potential of the BM as a site for islet allotransplantation.
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A preclinical evaluation of alternative site for islet allotransplantation. PLoS One 2017; 12:e0174505. [PMID: 28358858 PMCID: PMC5373587 DOI: 10.1371/journal.pone.0174505] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 03/10/2017] [Indexed: 02/05/2023] Open
Abstract
The bone marrow cavity (BMC) has recently been identified as an alternative site to the liver for islet transplantation. This study aimed to compare the BMC with the liver as an islet allotransplantation site in diabetic monkeys. Diabetes was induced in Rhesus monkeys using streptozocin, and the monkeys were then divided into the following three groups: Group1 (islets transplanted in the liver with immunosuppressant), Group 2 (islets transplanted in the tibial BMC), and Group 3 (islets transplanted in the tibial BMC with immunosuppressant). The C-peptide and blood glucose levels were preoperatively measured. An intravenous glucose tolerance test (IVGTT) was conducted to assess graft function, and complete blood cell counts were performed to assess cell population changes. Cytokine expression was measured using an enzyme-linked immune sorbent assay (ELISA) and MILLIPLEX. Five monkeys in Group 3 exhibited a significantly increased insulin-independent time compared with the other groups (Group 1: 78.2 ± 19.0 days; Group 2: 58.8 ± 17.0 days; Group 3: 189.6 ± 26.2 days) and demonstrated increases in plasma C-peptide 4 months after transplantation. The infusion procedure was not associated with adverse effects. Functional islets in the BMC were observed 225 days after transplantation using the dithizone (DTZ) and insulin/glucagon stains. Our results showed that allogeneic islets transplanted in the BMC of diabetic Rhesus monkeys remained alive and functional for a longer time than those transplanted in the liver. This study was the first successful demonstration of allogeneic islet engraftment in the BMC of non-human primates (NHPs).
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Iuamoto LR, Meyer A, Chaib E, D’Albuquerque LAC. Review of experimental attempts of islet allotransplantation in rodents: Parameters involved and viability of the procedure. World J Gastroenterol 2014; 20:13512-13520. [PMID: 25309081 PMCID: PMC4188902 DOI: 10.3748/wjg.v20.i37.13512] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Revised: 05/03/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
The purpose of the present study was to organize the parameters involved in experimental allotransplantation in rodents to elaborate the most suitable model to supply the scarcity of islet donors. We used the PubMed database to systematically search for published articles containing the keywords “rodent islet transplantation” to review. We included studies that involved allotransplantation experiments with rodents’ islets, and we reviewed the reference lists from the eligible publications that were retrieved. We excluded articles related to isotransplantation, autotransplantation and xenotransplantation, i.e., transplantation in other species. A total of 25 studies related to allotransplantation were selected for systematic review based on their relevance and updated data. Allotransplantation in rodents is promising and continues to develop. Survival rates of allografts have increased with the discovery of new immunosuppressive drugs and the use of different graft sites. These successes suggest that islet transplantation is a promising method to overcome the scarcity of islet donors and advance the treatment options for type 1 diabetes.
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Wright JR, Xu BY. That which does not kill us makes us stronger--does Nietzsche's quote apply to islets? A re-evaluation of the passenger leukocyte theory, free radicals, and glucose toxicity in islet cell transplantation. Med Hypotheses 2014; 83:92-8. [PMID: 24767938 DOI: 10.1016/j.mehy.2014.03.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 03/28/2014] [Indexed: 11/26/2022]
Abstract
In clinical islet transplantation, isolated islets are embolized into the liver via the portal vein (PV); however, up to 70% of the islets are lost in the first few days after transplantation (i.e., too quickly to be mediated by the adaptive immune system). Part of early loss is due to instant blood-mediated inflammatory reaction, an immune/thrombotic process caused by islets interacting with complement. We have shown that glucose toxicity (GT) also plays a critical role based upon the observation that islets embolized into the PVs of diabetic athymic mice are rapidly lost but, if recipients are not diabetic, the islet grafts persist. Using donor islets resistant to the β-cell toxin streptozotocin, we have shown that intraportal islets engrafted in non-diabetic athymic mice for as little as 3 days will maintain normoglycemia when streptozotocin is administered destroying the recipient's native pancreas β-cells. What is the mechanism of GT in β-cells? Chronic exposure to hyperglycemia over-exerts β-cells and their electron transport chains leak superoxide radicals during aerobic metabolism. Here we reinterpret old data and present some compelling new data supporting a new model of early intraportal islet graft loss. We hypothesize that diabetes stimulates overproduction of superoxide in both the β-cells of the islet grafts and the endothelial cells lining the intraportal microvasculature adjacent to where the embolized islets become lodged. This double dose of oxidant damage stresses both the islets, which are highly susceptible to free radicals because of inherent low levels of scavenging enzymes, and the adjacent hepatic endothelial cells. This, superimposed upon localized endothelial damage caused by embolization, precipitates inflammation and coagulation which further damages islet grafts. Based upon this model, we predict that pre-exposing islets to sub-lethal hyperoxia should up-regulate islet free radical scavenging enzyme levels and promote initial engraftment; reinterpretation of 30 years old "passenger leukocyte" data and preliminary new data support this. Other data suggests that pre-exposure of recipients to hyperoxia could up-regulate antioxidant enzymes in the hepatic endothelium. The combination of both effects could markedly enhance early intraportal islet graft survival and engraftment. Finally, if our model is correct, current in vitro and in vivo tests used to test batches of harvested islets for viability and function prior to transplantation are poorly conceived (n.b., it is already well-known that results using these tests often do not predict clinical islet transplantation success) and a different testing paradigm is suggested.
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Affiliation(s)
- J R Wright
- University of Calgary, Department of Pathology & Laboratory Medicine and Calgary Laboratory Services, Calgary, Alberta, Canada.
| | - B-Y Xu
- University of Calgary, Department of Pathology & Laboratory Medicine and Calgary Laboratory Services, Calgary, Alberta, Canada
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Meier RPH, Seebach JD, Morel P, Mahou R, Borot S, Giovannoni L, Parnaud G, Montanari E, Bosco D, Wandrey C, Berney T, Bühler LH, Muller YD. Survival of free and encapsulated human and rat islet xenografts transplanted into the mouse bone marrow. PLoS One 2014; 9:e91268. [PMID: 24625569 PMCID: PMC3953382 DOI: 10.1371/journal.pone.0091268] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 02/10/2014] [Indexed: 01/19/2023] Open
Abstract
Bone marrow was recently proposed as an alternative and potentially immune-privileged site for pancreatic islet transplantation. The aim of the present study was to assess the survival and rejection mechanisms of free and encapsulated xenogeneic islets transplanted into the medullary cavity of the femur, or under the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice. The median survival of free rat islets transplanted into the bone marrow or under the kidney capsule was 9 and 14 days, respectively, whereas that of free human islets was shorter, 7 days (bone marrow) and 10 days (kidney capsule). Infiltrating CD8+ T cells and redistributed CD4+ T cells, and macrophages were detected around the transplanted islets in bone sections. Recipient mouse splenocytes proliferated in response to donor rat stimulator cells. One month after transplantation under both kidney capsule or into bone marrow, encapsulated rat islets had induced a similar degree of fibrotic reaction and still contained insulin positive cells. In conclusion, we successfully established a small animal model for xenogeneic islet transplantation into the bone marrow. The rejection of xenogeneic islets was associated with local and systemic T cell responses and macrophage recruitment. Although there was no evidence for immune-privilege, the bone marrow may represent a feasible site for encapsulated xenogeneic islet transplantation.
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Affiliation(s)
- Raphael P. H. Meier
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Jörg D. Seebach
- Division of Clinical Immunology and Allergology, Department of Internal Medicine, University Hospital and Medical Faculty, Geneva, Switzerland
| | - Philippe Morel
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Redouan Mahou
- Institut d’Ingénierie Biologique et Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Sophie Borot
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Laurianne Giovannoni
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Geraldine Parnaud
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Elisa Montanari
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Domenico Bosco
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Christine Wandrey
- Institut d’Ingénierie Biologique et Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Thierry Berney
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Leo H. Bühler
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Yannick D. Muller
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
- Division of Clinical Immunology and Allergology, Department of Internal Medicine, University Hospital and Medical Faculty, Geneva, Switzerland
- * E-mail:
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Sakata N, Aoki T, Yoshimatsu G, Tsuchiya H, Hata T, Katayose Y, Egawa S, Unno M. Strategy for clinical setting in intramuscular and subcutaneous islet transplantation. Diabetes Metab Res Rev 2014; 30:1-10. [PMID: 24000195 DOI: 10.1002/dmrr.2463] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Revised: 07/09/2013] [Accepted: 08/27/2013] [Indexed: 01/08/2023]
Abstract
Intraportal islet transplantation has a long history as a procedure for clinical islet transplantation. However, many recent studies revealed that the intraportal procedure has some disadvantages in transplant efficiency and safety. Many candidates as an optimal transplant site for islets have been assessed, but further studies and clinical trials are still necessary. Intramuscular and subcutaneous spaces are important candidates, because the transplant and biopsy procedures are simple approaches with minimal invasion and few complications. Although they are sites with hypovascularity and hypoxia, which contribute to the poor transplant efficiency, many experimental trials for improving the outcome in intramuscular and subcutaneous islet transplantations have been performed, focusing on early angiogenesis and scaffolds for engrafting transplanted islets. We review current progress in intramuscular and subcutaneous islet transplantations and discuss ways to develop them as optimal transplant sites for islets.
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Affiliation(s)
- Naoaki Sakata
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
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Revascularization of transplanted pancreatic islets and role of the transplantation site. Clin Dev Immunol 2013; 2013:352315. [PMID: 24106517 PMCID: PMC3782812 DOI: 10.1155/2013/352315] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 08/09/2013] [Indexed: 12/16/2022]
Abstract
Since the initial reporting of the successful reversal of hyperglycemia through the transplantation of pancreatic islets, significant research efforts have been conducted in elucidating the process of revascularization and the influence of engraftment site on graft function and survival. During the isolation process the intrinsic islet vascular networks are destroyed, leading to impaired revascularization after transplant. As a result, in some cases a significant quantity of the beta cell mass transplanted dies acutely following the infusion into the portal vein, the most clinically used site of engraftment. Subsequently, despite the majority of patients achieving insulin independence after transplant, a proportion of them recommence small, supplemental exogenous insulin over time. Herein, this review considers the process of islet revascularization after transplant, its limiting factors, and potential strategies to improve this critical step. Furthermore, we provide a characterization of alternative transplant sites, analyzing the historical evolution and their role towards advancing transplant outcomes in both the experimental and clinical settings.
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Simulated microgravity combined with polyglycolic acid scaffold culture conditions improves the function of pancreatic islets. BIOMED RESEARCH INTERNATIONAL 2013; 2013:150739. [PMID: 24024182 PMCID: PMC3758870 DOI: 10.1155/2013/150739] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 06/01/2013] [Accepted: 06/16/2013] [Indexed: 01/13/2023]
Abstract
The in vitro culture of pancreatic islets reduces their immunogenicity and prolongs their availability for transplantation. Both simulated microgravity (sMG) and a polyglycolic acid scaffold (PGA) are believed to confer advantages to cell culture. Here, we evaluated the effects of sMG combined with a PGA on the viability, insulin-producing activity and morphological alterations of pancreatic islets. Under PGA-sMG conditions, the purity of the islets was ≥85%, and the islets had a higher survival rate and an increased ability to secrete insulin compared with islets cultured alone in the static, sMG, or PGA conditions. In addition, morphological analysis under scanning electron microscopy (SEM) revealed that the PGA-sMG treatment preserved the integral structure of the islets and facilitated islet adhesion to the scaffolds. These results suggest that PGA-sMG coculture has the potential to improve the viability and function of islets in vitro and provides a promising method for islet transplantation.
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Souza YEDMD, Chaib E, Lacerda PGDD, Crescenzi A, Bernal-Filho A, D'Albuquerque LAC. Islet transplantation in rodents. Do encapsulated islets really work? ARQUIVOS DE GASTROENTEROLOGIA 2012; 48:146-52. [PMID: 21709957 DOI: 10.1590/s0004-28032011000200011] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Accepted: 11/19/2010] [Indexed: 11/22/2022]
Abstract
CONTEXT Diabetes mellitus type I affects around 240 million people in the world and only in the USA 7.8% of the population. It has been estimated that the costs of its complications account for 5% to 10% of the total healthcare spending around the world. According to World Health Organization, 300 million people are expected to develop diabetes mellitus by the year 2025. The pancreatic islet transplantation is expected to be less invasive than a pancreas transplant, which is currently the most commonly used approach. OBJECTIVES To compare the encapsulated and free islet transplantation in rodents looking at sites of islet implantation, number of injected islets, viability and immunosuppression. METHODS A literature search was conducted using MEDLINE/PUBMED and SCIELO with terms about islet transplantation in the rodent from 2000 to 2010. We found 2,636 articles but only 56 articles from 2000 to 2010 were selected. RESULTS In these 56 articles used, 34% were encapsulated and 66% were nonencapsulated islets. Analyzing both types of islets transplantation, the majority of the encapsulated islets were implanted into the peritoneal cavity and the nonencapsulated islets into the liver, through the portal vein. In addition, the great advantage of the peritoneal cavity as the site of islet transplantation is its blood supply. Both vascular endothelial cells and vascular endothelial growth factor were used to stimulate angiogenesis of the islet grafts, increasing the vascularization rapidly after implantation. It also has been proven that there is influence of the capsules, since the larger the capsule more chances there are of central necrosis. In some articles, the use of immunosuppression demonstrated to increase the life expectancy of the graft. CONCLUSION While significant progress has been made in the islets transplantation field, many obstacles remain to be overcome. Microencapsulation provides a means to transplant islets without immunosuppressive agents and may enable the performance of xenotransplantation. The use of alternative donor sources, fewer islets per capsule and the appropriate deployment location, such as the peritoneal cavity, may give a future perspective to the application of immunoprotective capsules and viability in clinical practice. A variety of strategies, such as genetic engineering, co-encapsulation, improvement in oxygen supply or the establishment of hypoxia resistance will also improve the islet transplantation performance. It remains to be determined which combination of strategies with encapsulation can fulfill the promise of establishing a simple and safe transplantation as a cure for diabetes.
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Abstract
The liver is the current site of choice for pancreatic islet transplantation, even though it is far from being an ideal site because of immunologic, anatomic, and physiologic factors leading to a significant early graft loss. A huge amount of alternative sites have been used for islet transplantation in experimental animal models to provide improved engraftment and long-term survival minimizing surgical complications. The pancreas, gastric submucosa, genitourinary tract, muscle, omentum, bone marrow, kidney capsule, peritoneum, anterior eye chamber, testis, and thymus have been explored. Site-specific differences exist in term of islet engraftment, but few alternative sites have potential clinical translation and generally the evidence of a post-transplant islet function better than that reached after intraportal infusion is still lacking. This review discusses site-specific benefits and drawbacks taking into account immunologic, metabolic, and technical aspects to identify the ideal microenvironment for islet function and survival.
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Affiliation(s)
- Elisa Cantarelli
- San Raffaele Diabetes Research Institute, San Raffaele Scientific Institute, Milan, Italy.
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Improving islet transplantation: a road map for a widespread application for the cure of persons with type I diabetes. Curr Opin Organ Transplant 2010; 14:683-7. [PMID: 19779341 DOI: 10.1097/mot.0b013e328332c44c] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW The widespread application of replacement therapies for type I diabetes is at present limited by the side-effects of systemic immunosuppression. Results obtained in several animal models show that islet encapsulation can control the rejection process without systemic side-effects. However, results have, in general, been disappointing when transferred to large animal models or to humans. RECENT FINDINGS Growing insights into how cells respond to mechanical forces and surrounding extracellular matrixes indicate that differences in the Young's modulus (the resistance to deformation) between the implanted biomaterial and surrounding tissues induce inflammation and fibrosis. A valid approach would be to select for implantation a tissue having a higher value of the Young's modulus, for example, bone, allowing direct contact with the highly vascularized bone marrow providing nutrient and oxygen support as well as a rapid distribution of released insulin to the systemic circulation. SUMMARY Development of a biochamber with bone-integrating properties will allow initiation of clinical trials with allogeneic human islets, xenogeneic pig islets or insulin-producing cells generated from human embryonic stem cell (hESC)/inducible pluripotent stem cell (iPSC).
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Abstract
The liver is the current site for pancreatic islet transplantation, but has many drawbacks due to immunologic and nonimmunologic factors. We asked whether pancreatic islets could be engrafted in the bone marrow (BM), an easily accessible and widely distributed transplant site that may lack the limitations seen in the liver. Syngeneic islets engrafted efficiently in the BM of C57BL/6 mice rendered diabetic by streptozocin treatment. For more than 1 year after transplantation, these animals showed parameters of glucose metabolism that were similar to those of nondiabetic mice. Islets in BM had a higher probability to reach euglycemia than islets in liver (2.4-fold increase, P = .02), showed a compact morphology with a conserved ratio between alpha and beta cells, and affected bone structure only very marginally. Islets in BM did not compromise hematopoietic activity, even when it was strongly induced in response to a BM aplasia-inducing infection with lymphocytic choriomeningitis virus. In conclusion, BM is an attractive and safe alternative site for pancreatic islet transplantation. The results of our study open a research line with potentially significant clinical impact, not only for the treatment of diabetes, but also for other diseases amenable to treatment with cellular transplantation.
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Merani S, Toso C, Emamaullee J, Shapiro AMJ. Optimal implantation site for pancreatic islet transplantation. Br J Surg 2008; 95:1449-61. [PMID: 18991254 DOI: 10.1002/bjs.6391] [Citation(s) in RCA: 190] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Since the first report of successful pancreatic islet transplantation to reverse hyperglycaemia in diabetic rodents, there has been great interest in determining the optimal site for implantation. Although the portal vein remains the most frequently used site clinically, it is not ideal. About half of the islets introduced into the liver die during or shortly after transplantation. Although many patients achieve insulin independence after portal vein infusion of islets, in the long term most resume insulin injections. METHODS This review considers possible sites and techniques of islet transplantation in small and large animal models, and in humans. Metabolic, immunological and technical aspects are discussed. RESULTS AND CONCLUSION Many groups have sought an alternative site that might offer improved engraftment and long-term survival, together with reduced procedure-related complications. The spleen, pancreas, kidney capsule, peritoneum and omental pouch have been explored. The advantages and disadvantages of various sites are discussed in order to define the most suitable for clinical use and to direct future research.
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Affiliation(s)
- S Merani
- Surgical Medical Research Institute, University of Alberta, Edmonton, Canada
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