Field Of Islet Transplantation Research Articles

Advancements in innate immune regulation strategies in islet transplantation.

As a newly emerging organ transplantation technique, islet transplantation has shown the advantages of minimal trauma and high safety since it was first carried out. The proposal of the Edmonton protocol, which has been widely applied, was a breakthrough in this method. However, direct contact between islets and portal vein blood will cause a robust innate immune response leading to massive apoptosis of the graft, and macrophages play an essential role in the innate immune response. Therefore, therapeutic strategies targeting macrophages in the innate immune response have become a popular research topic in recent years. This paper will summarize and analyze recent research on strategies for regulating innate immunity, primarily focusing on macrophages, in the field of islet transplantation, including drug therapy, optimization of islet preparation process, islet engineering and Mesenchymal stem cells cotransplantation. We also expounded the heterogeneity, plasticity and activation mechanism of macrophages in islet transplantation, providing a theoretical basis for further research.

Challenges and opportunities in the islet transplantation microenvironment: a comprehensive summary of inflammatory cytokine, immune cells, and vascular endothelial cells.

It is now understood that islet transplantation serves as a β-cell replacement therapy for type 1 diabetes. Many factors impact the survival of transplanted islets, especially those related to the microenvironment. This review explored microenvironmental components, including vascular endothelial cells, inflammatory cytokines, and immune cells, and their profound effects on post-islet transplantation survival rates. Furthermore, it revealed therapeutic strategies aimed at targeting these elements. Current evidence suggests that vascular endothelial cells are pivotal in facilitating vascularization and nutrient supply and establishing a new microcirculation network for transplanted islets. Consequently, preserving the functionality of vascular endothelial cells emerges as a crucial strategy to enhance the survival of islet transplantation. Release of cytokines will lead to activation of immune cells and production and release of further cytokines. While immune cells hold undeniable significance in regulating immune responses, their activation can result in rejection reactions. Thus, establishing immunological tolerance within the recipient's body is essential for sustaining graft functionality. Indeed, future research endeavors should be directed toward developing precise strategies for modulating the microenvironment to achieve higher survival rates and more sustained transplantation outcomes. While acknowledging certain limitations inherent to this review, it provides valuable insights that can guide further exploration in the field of islet transplantation. In conclusion, the microenvironment plays a paramount role in islet transplantation. Importantly, we discuss novel perspectives that could lead to broader clinical applications and improved patient outcomes in islet transplantation.

1496-P: Resatorvid, an Inhibitor of Toll-Like Receptor-4, Protects Allogenic Islets from Inflammatory and Immune Response

Purpose: Loss of islet mass by instant blood mediated inflammatory reaction (IBMIR) and immunological rejection are major hurdles currently facing the field of islet transplantation. Toll-like receptor 4 (TLR4) plays a central role in inflammation and shaping adaptive immune response. We investigated the protective effects of resatorvid (TAK-242) using in vitro models of islet transplantation. Methods: Soluble TAK-242 or TAK-242 conjugated to the surface of islets utilizing copper-free click chemistry with a cleavable chemical linker were used. Islets were mixed with allogenic blood for a period of 3 hours and plasma levels of miRNA-375 and miRNA-200c were analyzed by RT-qPCR. Allogenic peripheral blood mononuclear cells were cultured with islets. T cell and monocyte activation were monitored by flow cytometry. Cytokine and miRNA levels in culture supernatant were measured by Luminex assay and RT-qPCR respectively. Results: The presence of TAK-242 in soluble form as well as released by cleavable linker from islet surface significantly reduced the release of miRNA-375 (p<0.01) and miRNA-200c (p<0.01) indicating less islet damage. In allogenic co-culture of islets and PBMCs, TAK-242 inhibited the expression of CD69 in T cells as well as decreased (p<0.05) the expression of CD86 and CD80 in monocytes. The production of cytokines IL-1β (p<0.001), IL-6 (p=0.01), IL-8 (p<0.05), IP10 (p<0.05), MCP-1 (p<0.001) and TNFα (p=0.005) in culture supernatant was decreased in the presence of soluble TAK-242 as well as TAK-242 released from islet surfaces. Conclusions: Inhibition of TLR4 using small molecule, TAK-242, protected islets from innate damage due to IBMIR as well as adaptive responses of activation of T cells and monocytes. These results validate the future study of inhibition of TLR4 using in vivo transplant model(s) to further investigate the efficacy of TLR4 inhibition to improve islet transplant survival and function. Disclosure J.D.Mattke: None. B.Naziruddin: None. B.Kane: None.

A Century-long Journey From the Discovery of Insulin to the Implantation of Stem Cell-derived Islets.

For the past century, insulin injections have saved millions of lives, but glycemic instability is still a persistent challenge for people with diabetes, leading to tremendous morbidity and premature mortality. Research in the field of islet transplantation has demonstrated that replacing insulin-producing β cells can restore euglycemia comparable to individuals without diabetes. However, a short supply of cadaveric islet donors, the technically challenging process of isolating islets, and the requirement for chronic immune suppression have impeded widespread clinical adoption. Rather than relying on cadaveric cells, pluripotent stem cells could serve as a virtually unlimited supply of insulin-producing β cells. Protocols have been developed that mimic the normal in vivo development of the human pancreas to generate pancreatic progenitor cells in vitro. Ongoing investigations have yielded progressively more mature β-like cells in vitro that produce insulin but do not yet fully mimic healthy mature β cells. Alongside development of differentiation protocols, other work has provided insight into potential implantation sites for stem cell-derived islet cells including the subcutaneous space, portal vein, and omentum. To optimize implanted cell survival and function, development of immune modulation therapies is ongoing, including selection of immunomodulatory medications and genetic modification of implanted cells to evade immune responses. Further, macroencapsulation or microencapsulation devices could be used to contain and/or immunoprotect implanted cells from the immune response including by using 3-dimensional bioprinting to facilitate the process. Remarkably, ongoing clinical trials have now yielded the first patient relying on differentiated stem cells rather than syringes as their insulin replacement therapy.

Artificial Cell Encapsulation for Biomaterials and Tissue Bio-Nanoengineering: History, Achievements, Limitations, and Future Work for Potential Clinical Applications and Transplantation.

Pancreatic β-cell loss and failure with subsequent deficiency of insulin production is the hallmark of type 1 diabetes (T1D) and late-stage type 2 diabetes (T2D). Despite the availability of parental insulin, serious complications of both types are profound and endemic. One approach to therapy and a potential cure is the immunoisolation of β cells via artificial cell microencapsulation (ACM), with ongoing promising results in human and animal studies that do not depend on immunosuppressive regimens. However, significant challenges remain in the formulation and delivery platforms and potential immunogenicity issues. Additionally, the level of impact on key metabolic and disease biomarkers and long-term benefits from human and animal studies stemming from the encapsulation and delivery of these cells is a subject of continuing debate. The purpose of this review is to summarise key advances in this field of islet transplantation using ACM and to explore future strategies, limitations, and hurdles as well as upcoming developments utilising bioengineering and current clinical trials.

P.169: Decellularized Cotyledons Isolated From Human Placenta Used Like a Scaffold for the Generation of a Human Bioartificial Pancreas

Background: Replacing damaged organs with biological substitutes capable of protecting the islets and facilitating vascularization is a great objective in the field of islet transplantation. A decellularized placenta includes a large number of cotyledons with a conserved vessel structure of the native organ. Our goal is to obtain a perfect decellularization protocol to generate pre-vascularized organoids by recellularizing this ECM with HUVECs and pancreatic islets. Methods: After blood removal, cotyledons were dissected from the placentas and decellularized using a bioreactor. Cell removal was assessed by histology and quantification of residual DNA. Presence of structural proteins and ECM structure were analyzed using SEM, CT scan and mass spectrometry. Recellularization protocols were conducted, with HUVECs or BOECs as endothelial cell sources, and with Ins-1E cells or rat islets as insulin secreting cell sources. Function of recellularized cotyledons was assessed in vitro with glucose stimulated insulin secretion tests (GSIS). To assess in vivo biocompatibility and function of the scaffolds, we transplanted in diabetic NSG mice. Glycaemia was measured every day to monitor normalization of blood glucose levels. Results: Our protocol led to successful decellularization, as evidenced by the absence of cells and the preserved ECM structure. Moreover, DNA quantification did not reveal any residual DNA. Quantification of GAG and hydroxyproline, and mass spectrometry analysis show that structural proteins are conserved. SEM and CT scan images revealed that the ECM structure was preserved after the decellularization protocol. Cells after recellularization showed a good vascularization after 7 days. The GSIS test shows a perfect organ response in the production of insulin. Conclusions: The decellularized cotyledon is the perfect scaffold to reproduce a prevascularized insulin-producing organ, which allows transplanted cells to survive during the peri-transplantation period.

Advances in Pancreatic Islet Transplantation Sites for the Treatment of Diabetes.

Diabetes is a complex disease that affects over 400 million people worldwide. The life-long insulin injections and continuous blood glucose monitoring required in type 1 diabetes (T1D) represent a tremendous clinical and economic burdens that urges the need for a medical solution. Pancreatic islet transplantation holds great promise in the treatment of T1D; however, the difficulty in regulating post-transplantation immune reactions to avoid both allogenic and autoimmune graft rejection represent a bottleneck in the field of islet transplantation. Cell replacement strategies have been performed in hepatic, intramuscular, omentum, and subcutaneous sites, and have been performed in both animal models and human patients. However more optimal transplantation sites and methods of improving islet graft survival are needed to successfully translate these studies to a clinical relevant therapy. In this review, we summarize the current progress in the field as well as methods and sites of islet transplantation, including stem cell-derived functional human islets. We also discuss the contribution of immune cells, vessel formation, extracellular matrix, and nutritional supply on islet graft survival. Developing new transplantation sites with emerging technologies to improve islet graft survival and simplify immune regulation will greatly benefit the future success of islet cell therapy in the treatment of diabetes.

Clinical use of donation after circulatory death pancreas for islet transplantation

Due to a shortage of donation after brain death (DBD) organs, donation after circulatory death (DCD) is increasingly performed. In the field of islet transplantation, there is uncertainty regarding the suitability of DCD pancreas in terms of islet yield and function after islet isolation. The aim of this study was to investigate the potential use of DCD pancreas for islet transplantation. Islet isolation procedures from 126 category 3 DCD and 258 DBD pancreas were performed in a 9‐year period. Islet yield after isolation was significantly lower for DCD compared to DBD pancreas (395 515 islet equivalents [IEQ] and 480 017 IEQ, respectively; p = .003). The decrease in IEQ during 2 days of culture was not different between the two groups. Warm ischemia time was not related to DCD islet yield. In vitro insulin secretion after a glucose challenge was similar between DCD and DBD islets. After islet transplantation, DCD islet graft recipients had similar graft function (AUC C‐peptide) during mixed meal tolerance tests and Igls score compared to DBD graft recipients. In conclusion, DCD islets can be considered for clinical islet transplantation.

Role of Exosomes in Islet Transplantation.

Exosomes are known for their ability to transport nucleic acid, lipid, and protein molecules, which allows for communication between cells and tissues. The cargo of the exosomes can have a variety of effects on a wide range of targets to mediate biological function. Pancreatic islet transplantation is a minimally invasive cell replacement therapy to prevent or reverse diabetes mellitus and is currently performed in patients with uncontrolled type 1 diabetes or chronic pancreatitis. Exosomes have become a focus in the field of islet transplantation for the study of diagnostic markers of islet cell viability and function. A growing list of miRNAs identified from exosomes collected during the process of isolating islets can be used as diagnostic biomarkers of islet stress and damage, leading to a better understanding of critical steps of the isolation procedure that can be improved to increase islet yield and quality. Exosomes have also been implicated as a possible contributor to islet graft rejection following transplantation, as they carry donor major histocompatibility complex molecules, which are then processed by recipient antigen-presenting cells and sensed by the recipient immune cells. Exosomes may find their way into the therapeutic realm of islet transplantation, as exosomes isolated from mesenchymal stem cells have shown promising results in early studies that have seen increased viability and functionality of isolated and grafted islets in vitro as well as in vivo. With the study of exosomes still in its infancy, continued research on the role of exosomes in islet transplantation will be paramount to understanding beta cell regeneration and improving long-term graft function.

Pancreatic Islets Quality and Potency Cannot be Verified as Required for Drugs: Reflection on the FDA Review of a Biological License Application for Human Islets.

Dear Editors Human pancreatic islets are regulated as a drug in the United States, requiring a biologic license application (BLA) approval for allotransplantation outside of clinical trials.1 The goal of the BLA is to prove that drug manufacturing consistently provides a well-defined, high-quality product, with verified characteristics that assure the desired clinical effect. Such verification is considered essential for clinical safety and efficacy of any drug. No US academic institutions have been capable of submitting a BLA for pancreatic islets over the last 20 y, which led to a gradual demise of the field.1 Recently, a private company has filed a BLA for human islets and the Food and Drug Administration (FDA) Advisory Committee members reviewed the application on April 15, 2021.2 Herein, we share findings from that meeting as they have major implications for the field of islet transplantation. FDA advisors confirmed that islet transplantation has a favorable benefit-risk profile for certain patients with type 1 diabetes. This conclusion is not surprising to the transplant community, as favorable clinical outcomes have been well documented over the last 20 y.1 However, the main question: whether the BLA should be approved, was not asked and remains unanswered. Moreover, during the meeting, the FDA presented its own analysis of the BLA data. FDA concluded that “the quality and potency of the human islets may not be reliably defined, and critical quality attributes of the islets (islet characteristics based on the release criteria) did not correlate with islet function.”2 Basically, this means that the main goal of the BLA has not been achieved. Thus, BLA approval has no merit. However, the final FDA decision is yet to be made. Based on the scientific evidence, we call on the FDA to reach the most rational decision: reject the BLA and allow human pancreatic islets to be included into the definition of human organs under the OPTN Final Rule. This will result in proper islet regulation, as with any other organ for transplantation. This was proposed in recent publications and directly to the FDA and Health and Human Services.3,4 Unfortunately, an FDA representative recently renounced our proposition.5 Alternatively, an FDA decision to reject the BLA but continue holding the same drug-related requirements would inevitably prevent any clinical use of human islets indefinitely in the United States. On the other hand, the FDA approval of a clearly deficient BLA would be detrimental. The BLA-holding commercial entity would be authorized to sell human islets of unverifiable quality and potency. Transplant centers will have no choice but to purchase and transplant them in patients. Such regulation would compromise patient safety and FDA credibility. Moreover, it would be impossible to verify the islet manufacturer performance, even when islet graft fails, since the ultimate reason for failure cannot be established. These new FDA findings provide further strong evidence that islets do not fit into drug regulatory framework and should be instead included into the organ for transplant regulations by the Health and Human Services Secretary.

COVID-19 and islet transplantation: Different twins.

For those who work in the field of islet transplantation, the microvascular coronavirus disease 2019 (COVID‐19) lung vessels obstructive thrombo‐inflammatory syndrome (recently referred to as MicroCLOTS) is familiar, as one cannot fail to recognize the presence of similarities with the instant blood mediated inflammatory reaction (IBMIR) occurring in the liver hours and days after islet infusion. Evidence in both MicroCLOTS and IBMIR suggests the involvement of the coagulation cascade and complement system activation and proinflammatory chemokines/cytokines release. Identification and targeting of pathway(s) playing a role as “master regulator(s)” in the post‐islet transplant detrimental inflammatory events could be potentially useful to suggest innovative COVID‐19 treatments and vice versa. Scientific organizations across the world are fighting the COVID‐19 pandemic. Islet transplantation, and more generally the transplantation scientific community, could contribute by suggesting strategies for innovative approaches. At the same time, in the near future, clinical trials in COVID‐19 patients will produce an enormous quantity of clinical and translational data on the control of inflammation and complement/microthrombosis activation. These data will represent a legacy to be transformed into innovation in the transplant field. It will be our contribution to change a dramatic event into advancement for the transplant field and ultimately for our patients.

High mobility group box 1 secretion blockade results in the reduction of early pancreatic islet graft loss

Pancreatic islet transplantation has been known as the best cure for patients suffering from severe type 1 diabetes mellitus (T1DM). Despite meaningful advances in human allogeneic islet transplantation field, significant amounts of islet loss in early post-transplantation periods is still a big concern for clinicians. One of the major factors determining the fate of the islets is the danger-associated molecular patterns (DAMPs) secreted by activated immune cells or islets themselves under hypoxic stress. High mobility group box 1 (HMGB1) protein is one of the best characterized DAMP molecules associated with islets. HMGB1 is known to be passively released by transplanted murine islet cells after taking damages from cytokines, reactive oxygen species, and other DAMPS, and the released HMGB1 harms neighboring islet cells by interacting with receptors expressed on murine islets such as toll-like receptor 2 (TLR2) and TLR4, thereby forming a vicious cycle. Here, we show that a small molecule inhibitor inflachromene (ICM) was capable of blocking the secretion of HMGB1 from murine islet cells during the normoxic and hypoxic post-isolation period. Notably, the treatment of ICM during the islet isolation process resulted in decreased HMGB1 levels during the subsequent cell culture. ICM's in vivo efficacy was evaluated in murine syngeneic islet transplantation model, and it significantly reduced the serum and graft level of HMGB1. Ultimately, the intraperitoneal administration of ICM prevented the loss of marginal-mass islet grafts and reversed the diabetes in mice.

Hydrogel materials for the application of islet transplantation

Type 1 diabetes mellitus is a serious disease comprising approximately 10% of all diabetes cases, and the global incidence of type 1 diabetes mellitus is steadily rising without any promise of a cure in the near future. Although islet transplantation has proven to be an effective means of treating type 1 diabetes mellitus and promoting insulin independence in patients, its widespread implementation has been severely constrained by instances of post-transplantation islet cell death, rejection, and severe adverse immune responses. Islet encapsulation is an active area of research aimed at shielding implanted islets from immunological rejection and inflammation while still allowing for effective insulin and nutrient exchange with donor cells. Given their promising physical and chemical properties, hydrogels have been a major subject of focus in the field of islet transplantation and encapsulation technology, offering promising advances towards immunologically privileged islet implants. The present review therefore summarizes the current state of research regarding the use of hydrogels in the context of islet transplantation, including both natural molecular hydrogels and artificial polymer hydrogels, with the goal of understanding the current strengths and weaknesses of this treatment strategy.

Development of a Simple In Vitro Assay to Assess Digestion of the Extracellular Matrix of the Human Pancreas by Collagenase Enzyme Blends

Despite huge advances in the field of islet transplantation over the last two decades, current islet isolation methods remain suboptimal, with transplantable yields obtained in less than half of all pancreases processed worldwide. Successful islet isolation is dependent on the ability of collagenase-based enzyme blends to digest extracellular matrix components at the islet–exocrine interface. The limited availability of donor pancreases hinders the use of full-scale islet isolations to characterize pancreas digestion by different enzyme components or blends, or allow the influence of inter-pancreatic variability between donors to be explored. We have developed a method that allows multiple enzyme components to be tested on any one pancreas. Biopsies of 0.5 cm3 were taken from seven standard (age ≥45) and eight young (age ≤35) pancreases. Serial cryosections were treated with Serva collagenase, neutral protease (NP), or the two enzymes together at clinically relevant concentrations. Following digestion, insulin and either collagen IV or laminin-α5 were detected by immunofluorescent labeling. Protein loss at the islet–exocrine interface was semi-quantified morphometrically, with reference to a control section. Differential digestion of the two proteins based on the enzyme components used was seen, with protein digestion significantly influenced by donor age. Treatment with collagenase and NP alone was significantly more effective at digesting collagen IV in the standard donor group, as was the NP mediated digestion of laminin-α5. Collagenase alone was not capable of significantly digesting laminin-α5 in either donor group. Combining the two enzymes ameliorated the age-related differences in the digestion of both proteins. No significant differences in protein loss were detected by the method when analyzed by two independent operators, demonstrating the reproducibility of the assay. The development of this simple yet reproducible assay has implications for both enzyme batch testing and identifying inter-donor digestion variability, while utilizing small amounts of both enzyme and human tissue.

The potential and challenges of alternative sources of β cells for the cure of type 1 diabetes.

The experience in the field of islet transplantation shows that it is possible to replace β cells in a patient with type 1 diabetes (T1D), but this cell therapy is limited by the scarcity of organ donors and by the danger associated to the immunosuppressive drugs. Stem cell therapy is becoming a concrete opportunity to treat various diseases. In particular, for a disease like T1D, caused by the loss of a single specific cell type that does not need to be transplanted back in its originating site to perform its function, a stem cell-based cell replacement therapy seems to be the ideal cure. New and infinite sources of β cells are strongly required. In this review, we make an overview of the most promising and advanced β cell production strategies. Particular hope is placed in pluripotent stem cells (PSC), both embryonic (ESC) and induced pluripotent stem cells (iPSC). The first phase 1/2 clinical trials with ESC-derived pancreatic progenitor cells are ongoing in the United States and Canada, but a successful strategy for the use of PSC in patients with diabetes has still to overcome several important hurdles. Another promising strategy of generation of new β cells is the transdifferentiation of adult cells, both intra-pancreatic, such as alpha, exocrine and ductal cells or extra-pancreatic, in particular liver cells. Finally, new advances in gene editing technologies have given impetus to research on the production of human organs in chimeric animals and on in situ reprogramming of adult cells through in vivo target gene activation.

Bibliometric analysis of the top-cited articles on islet transplantation.

Aims:To identify and characterize the top-cited articles in the field of islet transplantation.Methods:We used the Science Citation Index Expanded database to identify the most frequently cited articles published after 1900. Articles were evaluated using the following characteristics: citation number, publication year, study design, references, country and institution of origin, authorship, and journal. Keyword analysis and citation networks were used to analyze research trends.Results:The most frequently cited articles received between 146 and 2988 citations; the median was 291. All of the most frequently cited articles were published between 1972 and 2012, and 85 articles were published after 1990. The most popular study design involved basic science (75 articles). The leading countries were the United States (US) and Canada, and the leading institutions were the University of Alberta, Canada, and the University of Minnesota, in the US. Journals specializing in diabetes or transplantation published more than half of the articles (n = 53, 52%), with the journal Diabetes publishing the largest number (n = 30). No association was found between a journal's impact factor and the number of top-cited articles it published. There was no correlation between the number of citations and the number of years since publication, authors, participating institutions, or countries involved. Top-cited articles focused on 2 themes: the use of antirejection immunotherapy or biocompatible encapsulations to prolong graft survival, and assessments of the efficacy of islet transplants, in particular, islet allografts.Conclusions:Our study can help researchers to identify and decipher the characteristics of top-cited articles in the field of islet transplantation. Just as clinically successful allografts are carried out using the Edmonton protocol, autografts and xenografts should be similarly strengthened to solve problems relating to immune rejection and islet sources, respectively.

Novel Fusion Protein Targeting Mitochondrial DNA Improves Pancreatic Islet Functional Potency and Islet Transplantation Outcomes

Long-term graft survival is an ongoing challenge in the field of islet transplantation. With the growing demand for transplantable organs, therapies to improve organ quality and reduce the incidence of graft dysfunction are of paramount importance. We evaluated the protective role of a recombinant DNA repair protein targeted to mitochondria (Exscien I-III), as a therapeutic agent using a rodent model of pancreatic islet transplantation. We first investigated the effect of therapy on isolated rat islets cultured with pro-inflammatory cytokines (interleukin-1 β, interferon γ, and tumor necrosis factor α) for 48 h and documented a significant reduction in apoptosis by flow cytometry, improved viability by immunofluorescence, and conserved functional potency in vitro and in vivo in Exscien I-III-treated islets. We then tested the effect of therapy in systemic inflammation using a rat model of donor brain death (BD) sustained for a 6-h period. Donor rats were allocated to 4 groups: (non-BD + vehicle, non-BD + Exscien I-III, BD + vehicle, and BD + Exscien I-III) and treated with Exscien I-III (4 mg/kg) or vehicle 30 min after BD induction. Sham (non-BD)-operated animals receiving either Exscien I-III or vehicle served as controls. Islets purified from BD + Exscien I-III-treated donors showed a significant increase in glucose-stimulated insulin release in vitro when compared to islets from vehicle-treated counterparts. In addition, donor treatment with Exscien I-III attenuated the effects of BD and significantly improved the functional potency of transplanted islets in vivo. Our data indicate that mitochondrially targeted antioxidant therapy is a novel strategy to protect pancreas and islet quality from the deleterious effects of cytokines in culture and during the inflammatory response associated with donation after BD. The potential for rapid translation into clinical practice makes Exscien I-III an attractive therapeutic option for the management of brain-dead donors or as an additive to islets in culture after isolation setting.

The state of the art of islet transplantation and cell therapy in type 1 diabetes.

In patients with type 1 diabetes (T1D), pancreatic β cells are destroyed by a selective autoimmune attack and their replacement with functional insulin-producing cells is the only possible cure for this disease. The field of islet transplantation has evolved significantly from the breakthrough of the Edmonton Protocol in 2000, since significant advances in islet isolation and engraftment, together with improved immunosuppressive strategies, have been reported. The main limitations, however, remain the insufficient supply of human tissue and the need for lifelong immunosuppression therapy. Great effort is then invested in finding innovative sources of insulin-producing β cells. One old alternative with new recent perspectives is the use of non-human donor cells, in particular porcine β cells. Also the field of preexisting β cell expansion has advanced, with the development of new human β cell lines. Yet, large-scale production of human insulin-producing cells from stem cells is the most recent and promising alternative. In particular, the optimization of in vitro strategies to differentiate human embryonic stem cells into mature insulin-secreting β cells has made considerable progress and recently led to the first clinical trial of stem cell treatment for T1D. Finally, the discovery that it is possible to derive human induced pluripotent stem cells from somatic cells has raised the possibility that a sufficient amount of patient-specific β cells can be derived from patients through cell reprogramming and differentiation, suggesting that in the future there might be a cell therapy without immunosuppression.

THERAPY OF ENDOCRINE DISEASE: Islet transplantation for type 1 diabetes: so close and yet so far away.

Over the past decades, tremendous efforts have been made to establish pancreatic islet transplantation as a standard therapy for type 1 diabetes. Recent advances in islet transplantation have resulted in steady improvements in the 5-year insulin independence rates for diabetic patients. Here we review the key challenges encountered in the islet transplantation field which include islet source limitation, sub-optimal engraftment of islets, lack of oxygen and blood supply for transplanted islets, and immune rejection of islets. Additionally, we discuss possible solutions for these challenges.

The potential benefit of non-purified islets preparations for islet transplantation

Since the advent of islet transplantation, there has been a significant emphasis on the importance of islet purity despite an inevitable associated loss of islet mass during the purification process. One of the key elements of the 'Edmonton Protocol' for islet transplantation published in 2000 was an emphasis on the need for sequential transplants of highly purified islets (averaging 24% beta cell purity) and the close correlation between the numbers of islets transplanted and the success of the procedure. However, the emphasis on islet purity may warrant further consideration as auto transplantation of non-purified islets currently provides the most successful insulin independence rates within the field of islet transplantation. While the role of auto and allo immunity could contribute to the differences in the success rates it is clear that within the clinical setting, significant acinar and ductal contamination is well tolerated. However, one could go further and hypothesize that extra-insular tissue including acinar tissue, ductal tissue, peri-pancreatic lymph nodes and vascular tissue actually confer an advantage to islet survival/function and may even contribute to the insulin secreting capacity of the graft post transplant. As such this review will assess the influence of extra-insular pancreatic tissue on the results of islet transplantation based on published evidence and will also explore the possibility that non-islet pancreatic cells are capable of differentiating into a beta cell phenotype in vivo contributing to an ongoing regeneration of endocrine mass during the period following transplantation.