Source Of Insulin-producing Cells Research Articles

Development of pancreatic islet cells in the extrahepatic bile ducts of rats with experimentally-induced metabolic syndrome

Context There is data about the existence of some endocrine cells in the epithelial layer of the bile duct in humans and rats. Objective We evaluated Ghrelin-, Insulin-, Glucagon- and Somatostatin-positive cells in peribiliary glands, mast cells, and nerve fibres. Materials and methods Wistar rats were used for dietary manipulation with a 15% fructose solution for 12 weeks. Tissue samples were elaborated with immunohistochemistry for Insulin, Glucagon, Ghrelin, and Somatostatin. Glucose and lipid parameters were studied. Results In treated animals, Ghrelin+ and Insulin+ cells in perybiliary glands (PBGs) were significantly increased. In the male fructose group there was a significant increase of the homeostasis model assessment insulin resistance (HOMA-IR). Conclusions Stem/progenitor cells in extrahepatic bile tree (EHBT) could be a source of Insulin-producing cells in metabolic syndrome. Fructose treatment induces the increase of Ghrelin+ and Insulin+ cells in PBGs and the elevation of Insulin and Ghrelin plasma concentration.

Directed self-assembly of a xenogeneic vascularized endocrine pancreas for type 1 diabetes

Intrahepatic islet transplantation is the standard cell therapy for β cell replacement. However, the shortage of organ donors and an unsatisfactory engraftment limit its application to a selected patients with type 1 diabetes. There is an urgent need to identify alternative strategies based on an unlimited source of insulin producing cells and innovative scaffolds to foster cell interaction and integration to orchestrate physiological endocrine function. We previously proposed the use of decellularized lung as a scaffold for β cell replacement with the final goal of engineering a vascularized endocrine organ. Here, we prototyped this technology with the integration of neonatal porcine islet and healthy subject-derived blood outgrowth endothelial cells to engineer a xenogeneic vascularized endocrine pancreas. We validated ex vivo cell integration and function, its engraftment and performance in a preclinical model of diabetes. Results showed that this technology not only is able to foster neonatal pig islet maturation in vitro, but also to perform in vivo immediately upon transplantation and for over 18 weeks, compared to normal performance within 8 weeks in various state of the art preclinical models. Given the recent progress in donor pig genetic engineering, this technology may enable the assembly of immune-protected functional endocrine organs.

Isolation of Rat Adipose Tissue Mesenchymal Stem Cells for Differentiation into Insulin-producing Cells.

Mesenchymal stem cells (MSCs)-especially those isolated from adipose tissue (Ad-MSCs)-have gained special attention as a renewable, abundant source of stem cells that does not pose any ethical concerns. However, current methods to isolate Ad-MSCs are not standardized and employ complicated protocols that require special equipment. We isolated Ad-MSCs from the epididymal fat of Sprague-Dawley rats using a simple, reproducible method. The isolated Ad-MSCs usually appear within 3 days post isolation, as adherent cells display fibroblastic morphology. Those cells reach 80% confluency within 1 week of isolation. Afterward, at passage 3-5 (P3-5), a full characterization was carried out for the isolated Ad-MSCs by immunophenotyping for characteristic MSC cluster of differentiation (CD) surface markers such as CD90, CD73, and CD105, as well as inducing differentiation of these cells down the osteogenic, adipogenic, and chondrogenic lineages. This, in turn, implies the multipotency of the isolated cells. Furthermore, we induced the differentiation of the isolated Ad-MSCs toward the insulin-producing cells (IPCs) lineage via a simple, relatively short protocol by incorporating high glucose Dulbecco's modified Eagle medium (HG-DMEM), β-mercaptoethanol, nicotinamide, and exendin-4. IPCs differentiation was genetically assessed, firstly, via measuring the expression levels of specific β-cell markers such as MafA, NKX6.1, Pdx-1, and Ins1, as well as dithizone staining for the generated IPCs. Secondly, the assessment was also carried out functionally by a glucose-stimulated insulin secretion (GSIS) assay. In conclusion, Ad-MSCs can be easily isolated, exhibiting all MSC characterization criteria, and they can indeed provide an abundant, renewable source of IPCs in the lab for diabetes research.

Strategies to Improve the Safety of iPSC-Derived β Cells for β Cell Replacement in Diabetes.

Allogeneic islet transplantation allows for the re-establishment of glycemic control with the possibility of insulin independence, but is severely limited by the scarcity of organ donors. However, a new source of insulin-producing cells could enable the widespread use of cell therapy for diabetes treatment. Recent breakthroughs in stem cell biology, particularly pluripotent stem cell (PSC) techniques, have highlighted the therapeutic potential of stem cells in regenerative medicine. An understanding of the stages that regulate β cell development has led to the establishment of protocols for PSC differentiation into β cells, and PSC-derived β cells are appearing in the first pioneering clinical trials. However, the safety of the final product prior to implantation remains crucial. Although PSC differentiate into functional β cells in vitro, not all cells complete differentiation, and a fraction remain undifferentiated and at risk of teratoma formation upon transplantation. A single case of stem cell-derived tumors may set the field back years. Thus, this review discusses four approaches to increase the safety of PSC-derived β cells: reprogramming of somatic cells into induced PSC, selection of pure differentiated pancreatic cells, depletion of contaminant PSC in the final cell product, and control or destruction of tumorigenic cells with engineered suicide genes.

LSD1 inhibition yields functional insulin-producing cells from human embryonic stem cells

BackgroundHuman embryonic stem cells represent a potentially unlimited source of insulin-producing cells for diabetes therapy. While tremendous progress has been made in directed differentiation of human embryonic stem cells into IPCs in vitro, the mechanisms controlling its differentiation and function are not fully understood. Previous studies revealed that lysine-specific demethylase 1(LSD1) balanced the self-renewal and differentiation in human induced pluripotent stem cells and human embryonic stem cells. This study aims to explore the role of LSD1 in directed differentiation of human embryonic stem cells into insulin-producing cells.MethodsHuman embryonic stem cell line H9 was induced into insulin-producing cells by a four-step differentiation protocol. Lentivirus transfection was applied to knockdown LSD1 expression. Immunofluorescence assay and flow cytometry were utilized to check differentiation efficiency. Western blot was used to examine signaling pathway proteins and differentiation-associated proteins. Insulin/C-peptide release was assayed by ELISA. Statistical analysis between groups was carried out with one-way ANOVA tests or a student’s t test when appropriate.ResultsInhibition or silencing LSD1 promotes the specification of pancreatic progenitors and finally the commitment of functional insulin-producing β cells; Moreover, inhibition or silencing LSD1 activated ERK signaling and upregulated pancreatic progenitor associated genes, accelerating pre-maturation of pancreatic progenitors, and conferred the NKX6.1+ population with better proliferation ability. IPCs with LSD1 inhibitor tranylcypromine treatment displayed enhanced insulin secretion in response to glucose stimulation.ConclusionsWe identify a novel role of LSD1 inhibition in promoting IPCs differentiation from hESCs, which would be emerged as potential intervention for generation of functional pancreatic β cells to cure diabetes.

Insulin-producing organoids engineered from islet and amniotic epithelial cells to treat diabetes

Maintaining long-term euglycemia after intraportal islet transplantation is hampered by the considerable islet loss in the peri-transplant period attributed to inflammation, ischemia and poor angiogenesis. Here, we show that viable and functional islet organoids can be successfully generated from dissociated islet cells (ICs) and human amniotic epithelial cells (hAECs). Incorporation of hAECs into islet organoids markedly enhances engraftment, viability and graft function in a mouse type 1 diabetes model. Our results demonstrate that the integration of hAECs into islet cell organoids has great potential in the development of cell-based therapies for type 1 diabetes. Engineering of functional mini-organs using this strategy will allow the exploration of more favorable implantation sites, and can be expanded to unlimited (stem-cell-derived or xenogeneic) sources of insulin-producing cells.

β Cell Replacement Therapy: The Next 10 Years.

β cell replacement with either pancreas or islet transplantation has progressed immensely over the last decades with current 1- and 5-year insulin independence rates of approximately 85% and 50%, respectively. Recent advances are largely attributed to improvements in immunosuppressive regimen, donor selection, and surgical technique. However, both strategies are compromised by a scarce donor source. Xenotransplantation offers a potential solution by providing a theoretically unlimited supply of islets, but clinical application has been limited by concerns for a potent immune response against xenogeneic tissue. β cell clusters derived from embryonic or induced pluripotent stem cells represent another promising unlimited source of insulin producing cells, but clinical application is pending further advances in the function of the β cell like clusters. Exciting developments and rapid progress in all areas of β cell replacement prompted a lively debate by members of the young investigator committee of the International Pancreas and Islet Transplant Association at the 15th International Pancreas and Islet Transplant Association Congress in Melbourne and at the 26th international congress of The Transplant Society in Hong Kong. This international group of young investigators debated which modality of β cell replacement would predominate the landscape in 10 years, and their arguments are summarized here.

EFFECTS OF ADIPOSE TISSUE MESENCHYMAL STEM CELL THERAPY ON DIABETIC RATS

Background: Globally, diabetes mellitus has become one of the most common serious diseases to public health. Mesenchymal stem cells provide an alternative option for treatment of diabetes. Objective: Investigation of adipose tissue-derived stem cells (AT-MSCs) potential as an available less invasive source to produce insulin producing cells (IPCs). Material and methods: Forty female and ten male adult rats of Sprague Dawley strain between 8-9 weeks-old weighing 150-200 g were used. The male rats were used as donors for mesenchymal stem cells, while female rats were assigned to four groups: Group I (control group), Group II (diabetic group), Group III (diabetic group injected by 2 doses of phosphate buffer saline) and Group IV (diabetic rats treated with MSCs isolated from adipose tissue). At the end of the experiment, serum levels of glucose, HbA1c, C-peptide and lipid profile, as well as the genes expressing the pancreatic regeneration (Pdx1 and Neuro D) were determined for all groups. The study was confirmed by histopathological and immunohistochemical examination of pancreatic tissue specimens. Results: STZinjection significantly increases the blood glucose, HbA1c, cholesterol, TG and LDL levels; while C-peptide and HDL levels significantly decreased. Furthermore, marked pancreatic destruction was also detected by significant decrease of pancreatic genes (Pdx1 and Neuro D) expression. All these parameters showed improvement with adipose tissue stem cells therapy. This improvement could not reach the normal levels when compared to the normal control group. These results were supported by the results of histological examination of pancreatic tissues. Conclusion: AT-MSCs therapy possessed anti-diabetogenic actions that might be mediated by their reducing effect on the blood glucose, HbA1c, lipid profile and expression of Pdx1 and Neuro D genes. The study demonstrated the potentiality of AT-MSCs as a safer, more promising source of IPCs providing a possible future therapeutic option for diabetes.

Human iPS Cell-Derived Insulin Producing Cells Form Organoids In Vivo That Are Glucose Responsive in Diabetic Mice.

Type I diabetes (T1D) is a condition caused by autoimmune destruction of pancreatic β-cells. The consequences of T1D are dysregulation of metabolism with severe consequences for the cardiovascular system, nervous system and kidney function. Islet and whole pancreatic organ transplantation are the most effective ways to treat T1D. Unfortunately, the shortage of cadaveric organs is a major obstacle to the management of T1D patients. Thus, an alternative source of insulin producing cells (IPCs) could significantly improve patient treatment. Here, we seek to establish induced pluripotent stem (iPS) cells as a novel source of IPCs that are patient tailored, obviating the need for immunosuppression. If successful, such an alternative could provide for a novel unlimited source of IPCs. For the generation of IPCs, we hypothesized that 3D differentiation of iPS cells into IPCs enhances the efficiency of pancreatic endocrine differentiation due to the increased cell-cell contact and scaffold-embedded signaling, giving rise to superior organoids that more efficiently secrete insulin and are glucose responsive. Thus, we developed a novel matrigel culture platform for generating IPCs from human iPS cells. This process follows a few simple steps: first we drive iPS cells to form the endoderm through signaling with Activin A. These cells are then exposed to specific pancreatic growth factors that induce the expression of the pancreatic master regulator Pdx1, among other transcription factors. Subsequently the Pdx1+ pancreatic precursor cells are exposed to nicotinamide and IGF-1 for another 6-10 days. Subsequently, the cell clusters develop into large spheroids that appear solid or hollow. On staining for pancreatic hormones, the solid spheroids, but not the hollow vacuoles, were strongly positive for insulin. These IPCs partially secrete insulin in vitro after stimulation with high glucose. Remarkably, when placed under the kidney capsule of diabetic mice, they form organoids that display neovascularization and regulate hyperglycemia. Thus, our data show that dermal fibroblasts can be reprogrammed into iPS cells, which when assembled into high density cell clusters with access to matrigel signaling and pancreatic growth factors, can generate IPCs that are glucose responsive. This strategy provides an alternative source of IPCs with the potential for clinical management of T1D.

Skin deep: from dermal fibroblasts to pancreatic beta cells.

Type I diabetes (T1D) is a chronic autoimmune disease caused by pancreatic β-cell destruction induced by autoantibodies and autoreactive T cells. After significant reduction of the β-cell mass, diabetes sets in and can cause significant complications. It is estimated that more than 3 million Americans have T1D, and its prevalence among young individuals is progressively rising; however, the reasons for this increase are not known. Islet transplantation is recognized as the ultimate cure for T1D, but unfortunately, the severe scarcity of available islets makes it necessary to establish alternative sources of β-cells. Our lab seeks to establish human-induced pluripotent stem cells as an unlimited, novel source of insulin-producing cells (IPCs) that are patient-specific, obviating the requirement for immunosuppression. Although several reports have emerged demonstrating successful derivation of IPCs from human pluripotent stem cells, the efficiencies of derivation are inadequate and these IPCs do not respond to glucose stimulation in vitro. We reasoned that the use of a growth factor sequestering bioscaffold and promotion of cell-cell signaling through 3D clustering would enhance the generation of functionally superior IPCs compared to those derived by 2D differentiation. Here, we discuss a novel 3D platform for the generation of highly efficient human IPCs.

Derivation of insulin-producing beta-cells from human pluripotent stem cells.

Human embryonic stem cells have been advanced as a source of insulin-producing cells that could potentially replace cadaveric-derived islets in the treatment of type 1 diabetes. To this end, protocols have been developed that promote the formation of pancreatic progenitors and endocrine cells from human pluripotent stem cells, encompassing both embryonic stem cells and induced pluripotent stem cells. In this review, we examine these methods and place them in the context of the developmental and embryological studies upon which they are based. In particular, we outline the stepwise differentiation of cells towards definitive endoderm, pancreatic endoderm, endocrine lineages and the emergence of functional beta-cells. In doing so, we identify key factors common to many such protocols and discuss the proposed action of these factors in the context of cellular differentiation and ongoing development. We also compare strategies that entail transplantation of progenitor populations with those that seek to develop fully functional hormone expressing cells in vitro. Overall, our survey of the literature highlights the significant progress already made in the field and identifies remaining deficiencies in developing a pluripotent stem cell based treatment for type 1 diabetes.

Generation of insulin-producing cells from rat mesenchymal stem cells using an aminopyrrole derivative XW4.4

Type 1 diabetes mellitus (T1DM), a multisystem disease with both biochemical and anatomical/structural consequences, is a major health concern worldwide. Pancreatic islet transplantation provides a promising treatment for T1DM. However, the limited availability of islet tissue or new sources of insulin producing cells (IPCs) that are responsive to glucose hinder this promising approach. Though slow, the development of pancreatic beta-cell lines from rodent or human origin has been steadily progressing. Bone marrow-derived mesenchymal stem cells (MSCs) are multipotent, culture-expanded, non-hematopoietic cells that are currently being investigated as a novel cellular therapy. The in vitro differentiation potential of IPCs has raised hopes for a treatment of clinical diseases associated with autoimmunity.We screened for small molecules that induce pancreatic differentiation of IPCs. There are some compounds which showed positive effects on the DTZ staining. The aminopyrrole derivative compound XW4.4 which shows the best activity among them was found to induce pancreatic differentiation of rat MSCs (rMSCs). The in vitro studies indicated that treatment of rMSCs with compound XW4.4 resulted in differentiated cells with characteristics of IPCs including islet-like clusters, spherical, grape-like morphology, insulin secretion, positive for dithizone, glucose stimulation and expression of pancreatic endocrine cell marker genes. The data has also suggested that hepatocyte nuclear factor 3β (HNF 3β) may be involved in pancreatic differentiation of rMSCs when treated with XW4.4. Results indicate that XW4.4 induced rMSCs support the efforts to derive functional IPCs and serve as a means to alleviate limitations surrounding islet cell transplantation in the treatment of T1DM.

Generation of Transplantable Beta Cells for Patient-Specific Cell Therapy

Islet cell transplantation offers a potential cure for type 1 diabetes, but it is challenged by insufficient donor tissue and side effects of current immunosuppressive drugs. Therefore, alternative sources of insulin-producing cells and isletfriendly immunosuppression are required to increase the efficiency and safety of this procedure. Beta cells can be transdifferentiated from precursors or another heterologous (non-beta-cell) source. Recent advances in beta cell regeneration from somatic cells such as fibroblasts could circumvent the usage of immunosuppressive drugs. Therefore, generation of patient-specific beta cells provides the potential of an evolutionary treatment for patients with diabetes.

Pig islet for xenotransplantation in human: structural and physiological compatibility for human clinical application

Allogeneic islet transplantation has proven difficult because organ shortages are recurrent, several pancreas donors are often needed to treat one diabetic recipient, and the intrahepatic site of islet implantation may not be the most appropriate site. Thus, another source of insulin-producing cells would be beneficial; and pigs represent a possible and viable source for obtaining such cells. Although the use of pig islet grafts appears to be difficult because of the species barrier, recent reports demonstrated that pig islet xenotransplantation can overcome the immunological barrier following strong immunosuppression and function successfully in primates for at least 6 months. Before becoming clinically applicable, however, pig islet xenotransplantation must still overcome the structural and physiological incompatibility between pig donor and human recipient. Researchers agree that it is necessary to produce more preclinical data in the pig-to-primate model before any pig-to-human transplantation of islets can be considered. Therefore, in this review, we provide a summary of the present state of knowledge about pig and human islet compatibility.

Enhanced Differentiation of Human Adipose Tissue-derived Stromal Cells into Insulin-producing Cells with Glucagon-like Peptide-1

Type 1 diabetes mellitus (T1DM) is mainly caused by reduction of the endogenous insulin secretion due to autoimmune destruction of pancreatic β cells, and a promising therapeutic approach for T1DM is pancreas and islet cell replacement. The major obstacle is the limited source of insulin-producing cells. Here, we report an efficient approach to induce human adipose-derived stromal cells (hADSCs) to differentiate into insulin-producing cells, with glucagon-like peptide-1 (GLP-1). hADSCs were successfully isolated from the adipose tissue, with adipogenic and osteogenic differentiation potency. Islet-like cell clusters formed in the culture, which was enhanced with the treatment of GLP-1. Reverse transcription polymerase chain reaction analysis showed the expression of the pancreas-related genes in the differentiated cells, such as pdx-1, ngn3, insulin, glucagon, somatostatin, glucokinase n and glut2. Immunocytochemical analysis showed that the induced cells co-expressed insulin, C-peptide and PDX-1. The GLP-1 receptor was present in the differentiated cells. In addition, flow cytometry analysis and ELISA showed that, in the presence of GLP-1, the percentage of insulin-producing cells was increased from 5.9% to 28.0% and the release of insulin increased from 9.53±0.7 pmol/106 cells to 15.86±1.3 pmol/106 cells. Insulin was released in response to glucose stimulation in a manner comparable to that of adult human islets. These results indicated that hADSCs isolated from adipose tissues can be induced to differentiate into insulin-producing cells, which is further enhanced with the treatment of GLP-1. These findings confirm that the differentiation of hADSCs to insulin-producing cells is indeed possible and indicate that the differentiated insulin-producing cells can be used as a potential source for transplantation into patients with T1DM.

Spontaneous In Vivo Differentiation of Embryonic Stem Cell-Derived Pancreatic Endoderm-Like Cells Corrects Hyperglycemia in Diabetic Mice

Whole pancreas and islet transplantation are currently used for the treatment of type 1 diabetes. However, the major limitations of this potentially curative approach are an inadequate supply of cadaveric pancreata, lifelong immunosuppression, and chronic graft rejection. Therefore, there is an urgent need to develop new sources of insulin-producing cells (IPCs). Here, we investigated whether embryonic stem (ES) cells can be exploited for the derivation of IPCs, and whether their transplantation can correct hyperglycemia in diabetic mice. ES cells engineered to express pancreatic and duodenal homeobox 1 (Pdx1), a critical pancreatic transcription factor, were differentiated into pancreatic endoderm-like cells (PELCs) and evaluated for their potential to correct hyperglycemia after transplantation in diabetic mice. After systemic injection, PELCs localized to the pancreas, liver, and kidney. They then spontaneously differentiated into IPCs that corrected hyperglycemia in diabetic mice. When transplanted under the kidney capsule, PELC-derived IPCs were equally efficient at correcting hyperglycemia. Real-time noninvasive in vivo bioluminescence imaging (BLI) of rat insulin promoter (RIP)-driven luciferase was used to monitor the fate of the transplanted PELCs. To confirm that the transplanted cells were responsible for the correction of hyperglycemia, kidneys containing the transplanted cells were nephrectomized, causing rapid hyperglycemia. Interestingly, none of the animals transplanted with PELCs developed tumors, a potential consequence of the differentiation and purification procedures. Our data suggest that Pdx1-expressing PELCs are capable of spontaneously undergoing differentiation in vivo into IPCs and leading to a sustained correction of hyperglycemia in diabetic mice.

Pig islets for clinical islet xenotransplantation

Allogeneic islet transplantation faces difficulties because organ shortage is recurrent; several pancreas donors are often needed to treat one diabetic recipient; and the intrahepatic site of islet implantation may not be the most appropriate one. Another source of insulin-producing cells, therefore, would be of major interest, and pigs represent a possible and serious source for obtaining such cells. Pig islet grafts may appear difficult because of the species barrier, but recent studies demonstrate that pig islets may function in diabetic primates for at least 6 months. Pig islet xenotransplantation, however, must still overcome the selection of a suitable pig donor to translate preclinical findings into clinical applications. This review summarizes the actual acquired knowledge of pig islet transplantation in primates to select the 'ideal' pig donor.

Are stem cells a cure for diabetes?

With the already heightened demand placed on organ donation, stem cell therapy has become a tantalizing idea to provide glucose-responsive insulin-producing cells to Type 1 diabetic patients as an alternative to islet transplantation. Multiple groups have developed varied approaches to create a population of cells with the appropriate characteristics. Both adult and embryonic stem cells have received an enormous amount of attention as possible sources of insulin-producing cells. Although adult stem cells lack the pluripotent nature of their embryonic counterparts, they appear to avoid the ethical debate that has centred around the latter. This may limit the eventual application of embryonic stem cells, which have already shown promise in early mouse models. One must also consider the potential of stem cells to form teratomas, a complication which would prove devastating in an immunologically compromised transplant recipient. The present review looks at the progress to date in both the adult and embryonic stem cells fields as potential treatments for diabetes. We also consider some of the limitations of stem cell therapy and the potential complications that may develop with their use.

Adult mouse intrahepatic biliary epithelial cells induced in vitro to become insulin-producing cells

Transdifferentiation of cells from a patient's own liver into pancreatic beta-cells could be useful for beta-cell replacement. We hypothesized that intrahepatic biliary epithelial cells (IHBECs) could become a new source of insulin-producing cells. IHBECs isolated from adult mice were expanded using our novel culture method termed, collagen-embedded floating culture method (CEFCM). With CEFCM, IHBECs formed three-dimensional ductal cysts and rapidly expanded their number by about 15-fold within 2 weeks. Over 90% of cells were positive for cytokeratin 7 and 19. At day 14, IHBECs were transfected with adenoviral (Ad)- pancreas duodenum homeobox 1 (Pdx-1), NeuroD or Pdx-1/VP16. After 7 additional days in serum- and insulin-free differentiation medium (DM), cell phenotypes were determined by RT-PCR, immunostaining and ELISA for insulin. In DM control IHBECs started to express some endocrine progenitor genes (Neurog3, NeuroD, Nkx6.1, and Pdx-1) but lacked insulin gene (Ins) mRNA. Transduced expression of PDX-1, NEUROD or PDX-1/VP16 led to expression of not only INS but also GLUT2 and prohormone convertase 1 and 2. About 3% of 4000 cells counted in PDX-1/VP16 transduced cultures stained strongly for C-peptide suggesting that a subpopulation may have the capacity for differentiation. Transduced cells released insulin (Ad-PDX-1 0.08+/-0.05, Ad-NEUROD 0.33+/-0.09, Ad-PDX-1/VP16 0.37+/-0.14 ng/1x10(5) cells after 48 h in culture). IHBECs can be markedly expanded, and then with molecular manipulation a subpopulation of these cells can differentiate towards a beta-cell phenotype. This approach may lead to a new source of beta-cells that can be used for transplantation in diabetes.

Pig Islet Xenotransplantation Into Non-human Primate Model

Allogeneic islet transplantation faces difficulties because (1) organ shortage is recurrent; (2) several pancreas donors are often needed to treat one diabetic recipient; and (3) the intrahepatic site of islet implantation may not be the most appropriate site. Another source of insulin-producing cells, therefore, would be of major interest, and pigs represent a possible and serious source for obtaining such cells. Pig islet grafts may seem difficult because of the species barrier, but recent reports demonstrate that pig islets may function in primates for at least 6 months. Pig islet xenotransplantation, however, must still overcome several hurdles before becoming clinically applicable. The actual consensus is to produce more preclinical data in the pig-to-primate model as a necessary requirement to envisage any pig-to-human transplantation of islets; therefore, a summary of the actual acquired knowledge of pig islet transplantation in primates seemed useful and is summarized in this overview.