Inhibition of apoptosis by survivin improves transplantation of pancreatic islets for treatment of diabetes in mice.
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ABSTRACT:
SUBMITTER: Dohi T
PROVIDER: S-EPMC1456913 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Type 1 diabetes is an autoimmune disease caused by permanent destruction of insulin-producing pancreatic ? cells and requires lifelong exogenous insulin therapy. Recently, islet transplantation has been developed, and although there have been significant advances, this approach is not widely used clinically due to the poor survival rate of the engrafted islets. We hypothesized that improving survival of engrafted islets through ex vivo genetic engineering could be a novel strategy for successful islet transplantation. We transduced islets with adenoviruses expressing betacellulin, an epidermal growth factor receptor ligand, which promotes ?-cell growth and differentiation, and transplanted these islets under the renal capsule of streptozotocin-induced diabetic mice. Transplantation with betacellulin-transduced islets resulted in prolonged normoglycemia and improved glucose tolerance compared with those of control virus-transduced islets. In addition, increased microvascular density was evident in the implanted islets, concomitant with increased endothelial von Willebrand factor immunoreactivity. Finally, cultured islets transduced with betacellulin displayed increased proliferation, reduced apoptosis and enhanced glucose-stimulated insulin secretion in the presence of cytokines. These experiments suggest that transplantation with betacellulin-transduced islets extends islet survival and preserves functional islet mass, leading to a therapeutic benefit in type 1 diabetes.
| S-EPMC4044676 | biostudies-literature
Project description:Since the late 20th century, advances in pancreatic islet transplantation have targeted improved glycemic control and fewer hypoglycemic events in patients with type 1 diabetes, and some important milestones have been reached. Following the Edmonton group's success in achieving insulin independence in all transplanted patients with type 1 diabetes, clinical islet transplantation is now performed worldwide. ? cell replacement therapy for type 1 diabetes was established based on the favorable outcomes of a phase 3, prospective, open-label, single-arm, clinical study conducted at 8 centers in North America, in which 42 of 48 patients who underwent islet transplantation from 2008 to 2011 achieved HbA1c < 7.0% (53 mmol/mol) at day 365, which was maintained at 2 years in 34 patients. In Japan, a phase 2 multicenter clinical trial of islet transplantation for type 1 diabetes patients is currently ongoing and will end soon, but the interim results have already led to positive changes, with allogeneic islet transplantation being covered by the national health insurance system since April 2020. Current efforts are being made to solve the problem of donor shortage by studying alternative donor sources, such as porcine islets and pancreatic progenitor cells derived from pluripotent stem cells. The results of clinical trials in this area are eagerly awaited. It is hoped that they will contribute to establishing alternative sources for insulin-producing ? cells in the near future.
| S-EPMC7731068 | biostudies-literature
Project description:INTRODUCTION: With the shortage of donor organs for islet transplantation, insulin-producing cells have been generated from different types of stem cell. Human fetal pancreatic stem cells have a better self-renewal capacity than adult stem cells and can readily differentiate into pancreatic endocrine cells, making them a potential source for islets in diabetes treatment. In the present study, the functions of pancreatic islets derived from human fetal pancreatic progenitor cells were evaluated in vitro and in vivo. METHODS: Human pancreatic progenitor cells isolated from the fetal pancreas were expanded and differentiated into islet endocrine cells in culture. Markers for endocrine and exocrine functions as well as those for alpha and beta cells were analyzed by immunofluorescent staining and enzyme-linked immunosorbent assay (ELISA). To evaluate the functions of these islets in vivo, the islet-like structures were transplanted into renal capsules of diabetic nude mice. Immunohistochemical staining for human C-peptide and human mitochondrion antigen was applied to confirm the human origin and the survival of grafted islets. RESULTS: Human fetal pancreatic progenitor cells were able to expand in medium containing basic fibroblast growth factor (bFGF) and leukemia inhibitor factor (LIF), and to differentiate into pancreatic endocrine cells with high efficiency upon the actions of glucagon-like peptide-1 and activin-A. The differentiated cells expressed insulin, glucagon, glucose transporter-1 (GLUT1), GLUT2 and voltage-dependent calcium channel (VDCC), and were able to aggregate into islet-like structures containing alpha and beta cells upon suspension. These structures expressed and released a higher level of insulin than adhesion cultured cells, and helped to maintain normoglycemia in diabetic nude mice after transplantation. CONCLUSIONS: Human fetal pancreatic progenitor cells have good capacity for generating insulin producing cells and provide a promising potential source for diabetes treatment.
| S-EPMC4055010 | biostudies-literature
Project description:During hematopoietic stem cell transplantation, a substantial number of donor cells are lost because of apoptotic cell death. Transplantation-associated apoptosis is mediated mainly by the proapoptotic BCL-2 family proteins BIM and BMF, and their proapoptotic function is conserved between mouse and human stem and progenitor cells. Permanent inhibition of apoptosis in donor cells caused by the loss of these BH3-only proteins improves transplantation outcome, but recipients might be exposed to increased risk of lymphomagenesis or autoimmunity. Here, we address whether transient inhibition of apoptosis can serve as a safe but efficient alternative to improve the outcome of stem cell transplantation. We show that transient apoptosis inhibition by short-term overexpression of prosurvival BCL-XL, known to block BIM and BMF, is not only sufficient to increase the viability of hematopoietic stem and progenitor cells during engraftment but also improves transplantation outcome without signs of adverse pathologies. Hence, this strategy represents a promising and novel therapeutic approach, particularly under conditions of limited donor stem cell availability.
| S-EPMC5626392 | biostudies-literature
Project description:Cryopreservation offers the potential to increase the availability of pancreatic islets for treatment of diabetic patients. However, current protocols, which use dimethyl sulfoxide (DMSO), lead to poor cryosurvival of islets. We demonstrate that equilibration of mouse islets with small molecules in aqueous solutions can be accelerated from > 24 to 6 h by increasing incubation temperature to 37 °C. We utilize this finding to demonstrate that current viability staining protocols are inaccurate and to develop a novel cryopreservation method combining DMSO with trehalose pre-incubation to achieve improved cryosurvival. This protocol resulted in improved ATP/ADP ratios and peptide secretion from β-cells, preserved cAMP response, and a gene expression profile consistent with improved cryoprotection. Our findings have potential to increase the availability of islets for transplantation and to inform the design of cryopreservation protocols for other multicellular aggregates, including organoids and bioengineered tissues.
| S-EPMC8129116 | biostudies-literature
Project description:Because of the fragility of isolated hepatocytes, extremely poor engraftment of transplanted hepatocytes remains a severe issue in hepatocyte transplantation. Therefore, improving hepatocyte engraftment is necessary to establish hepatocyte transplantation as a standard therapy. Since the pancreatic islets are known to have favorable autocrine effects, we hypothesized that the transplanted islets might influence not only the islets but also the nearby hepatocytes, subsequently promoting engraftment. We evaluated the effects of islet co-transplantation using an analbuminemic rat model (in vivo model). Furthermore, we established a mimicking in vitro model to investigate the underlying mechanisms. In an in vivo model, the hepatocyte engraftment was significantly improved only when the islets were co-transplanted to the nearby hepatocytes (p < 0.001). Moreover, the transplanted hepatocytes appeared to penetrate the renal parenchyma together with the co-transplanted islets. In an in vitro model, the viability of cultured hepatocytes was also improved by coculture with pancreatic islets. Of particular interest, the coculture supernatant alone could also exert beneficial effects comparable to islet coculture. Although insulin, VEGF, and GLP-1 were selected as candidate crucial factors using the Bio-Plex system, beneficial effects were partially counteracted by anti-insulin receptor antibodies. In conclusion, this study demonstrated that islet co-transplantation improves hepatocyte engraftment, most likely due to continuously secreted crucial factors, such as insulin, in combination with providing favorable circumstances for hepatocyte engraftment. Further refinements of this approach, especially regarding substitutes for islets, could be a promising strategy for improving the outcomes of hepatocyte transplantation.
| S-EPMC8048420 | biostudies-literature
Project description:Immune rejection after transplantation is common, which leads to prompt failure of the graft. Therefore, to prolong the survival time of the graft, immunosuppressive therapy is the norm. Here, we report a robust immune protection protocol using FK506-loaded microspheres (FK506M) in injectable hydrogel. Pancreatic islets were codelivered with the FK506M into the subcutaneous space of streptozocin-induced diabetic mice. The islets codelivered with 10 mg/kg FK506M maintained normal blood glucose levels during the study period (survival rate: 60%). However, transplantation of islets and FK506M at different sites hardly controlled the blood glucose level (survival rate: 20%). Immunohistochemical analysis revealed an intact morphology of the islets transplanted with FK506M. In addition, minimal number of immune cells invaded inside the gel of the islet-FK506M group. The single injection of FK506M into the local microenvironment effectively inhibited immune rejection and prolonged the survival time of transplanted islets in a xenograft model.
| S-EPMC8241191 | biostudies-literature
Project description:Type 2 diabetes is a common metabolic disorder related to insulin resistance, or deficiency of insulin secretion, caused by decreased insulin sensitivity and destruction of islet structure and function. As the second human genome, the microbiota has been observed to have a growing relationship with diabetes in recent years. Microbiota imbalance has been hypothesized to be involved in the regulation of energy metabolism and the inflammatory immune response in diabetes. The present study aimed to investigate whether fecal microbiota transplantation (FMT) could alleviate the symptoms associated with type 2 diabetes. To this end, a type 2 diabetes mouse model was first established through the consumption of a high-fat diet combined with streptozotocin (100 mg/kg), and FMT was used to rebuild the gut microbiota of diabetic mice. Fasting blood glucose, oral glucose tolerance tests, and HbA1c levels were monitored, while the hypoglycemic effects of FMT were also observed. Insulin levels were tested by ELISA and related indexes such as HOMA-IR, HOMA-IS, and HOMA-β were calculated. We found that insulin resistance and pancreatic islet β-cells were improved after FMT treatment. Meanwhile, the markers of inflammation in the pancreatic tissue were detected by ELISA and immunohistochemistry, which indicated that inflammatory response decreased following FMT treatment. Furthermore, flow cytometry and western blot results revealed that FMT inhibited the β-cell apoptosis. Here, the effect of FMT on hypoglycemia in type 2 diabetes was addressed by improving insulin resistance and repairing impaired islets, thereby providing a potential treatment strategy for type 2 diabetes.
| S-EPMC6979041 | biostudies-literature
Project description:In pancreatic islets, catabolism of tryptophan into serotonin and serotonin receptor 2B (HTR2B) activation is crucial for β-cell proliferation and maternal glucose regulation during pregnancy. Factors that reduce serotonin synthesis and perturb HTR2B signaling are associated with decreased β-cell number, impaired insulin secretion, and gestational glucose intolerance in mice. Albeit the tryptophan-serotonin pathway is dependent on vitamin B6 bioavailability, how vitamin B6 deficiency impacts β-cell proliferation during pregnancy has not been investigated. In this study, we created a vitamin B6 deficient mouse model and investigated how gestational deficiency influences maternal glucose tolerance. Our studies show that gestational vitamin B6 deficiency decreases serotonin levels in maternal pancreatic islets and reduces β-cell proliferation in an HTR2B-dependent manner. These changes were associated with glucose intolerance and insulin resistance, however insulin secretion remained intact. Our findings suggest that vitamin B6 deficiency-induced gestational glucose intolerance involves additional mechanisms that are complex and insulin independent.
| S-EPMC7998034 | biostudies-literature
Project description:ObjectiveNo previous study has measured the oxygenation of intraportally transplanted islets, although recent data suggest that insufficient engraftment may result in hypoxia and loss of islet cells.Research design and methodsAfter intraportal infusion into syngeneic mice, islet oxygenation was investigated in 1-day-old, 1-month-old, or 3-month-old grafts and compared with renal subcapsular grafts and native islets. Animals received an intravenous injection of pimonidazole for immunohistochemical detection of low-oxygenated islet cells (pO(2) <10 mmHg), and caspase-3 immunostaining was performed to assess apoptosis rates in adjacent tissue sections.ResultsIn the native pancreas of nontransplanted animals, ?30% of the islets stained positive for pimonidazole. In 1-day-old and 1-month-old grafts, the percentage of pimonidazole-positive islets in the liver was twice that of native islets, whereas this increase was abolished in 3-month-old grafts. Beneath the renal capsule, pimonidazole accumulation was, however, similar to native islets at all time points. Apoptosis rates were markedly increased in 1-day-old intrahepatic grafts compared with corresponding renal islet grafts, which were slightly increased compared with native islets. One month posttransplantation renal subcapsular grafts had similar frequencies of apoptosis as native islets, whereas apoptosis in intraportally implanted islets was still high. In the liver, islet graft vascular density increased between 1 and 3 months posttransplantation, and apoptosis rates simultaneously dropped to values similar to those observed in native islets.ConclusionsThe vascular engraftment of intraportally transplanted islets is markedly delayed compared with renal islet grafts. The prolonged ischemia of intraportally transplanted islets may favor an alternative implantation site.
| S-EPMC3161309 | biostudies-literature