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Project description:The RANBP2/Importin-7-FOXO1 axis provides superior cold protection to aid islet transplantation
| PRJNA767830 | ENA
Project description:Aims/hypothesisIslet transplantation is a promising treatment for type 1 diabetes but is hampered by a shortage of donor human tissue and early failure. Research on islet cell transplantation includes finding new sources of cells and immunoisolation to protect from immune assault and tumourigenic potential. Small islet cell aggregates were studied to determine if their survival and function were superior to intact islets within microcapsules because of reduced oxygen transport limitation and inflammatory mediators.MethodsIslet cell aggregates were generated by dispersing rat islets into single cells and allowing them to re-aggregate in culture. Rat islets and islet cell aggregates were encapsulated in barium alginate capsules and studied when cultured in low (0.5% or 2%) or normal (20%) oxygen, or transplanted into mice.ResultsEncapsulated islet cell aggregates were able to survive and function better than intact islets in terms of oxygen-consumption rate, nuclei counts, insulin-to-DNA ratio and glucose-stimulated insulin secretion. They also had reduced expression of pro-inflammatory genes. Islet cell aggregates showed reduced tissue necrosis in an immunodeficient transplant model and a much greater proportion of diabetic xenogeneic transplant recipients receiving islet cell aggregates (tissue volume of only 85 islet equivalents) had reversal of hyperglycaemia than recipients receiving intact islets.Conclusions/interpretationThese aggregates were superior to intact islets in terms of survival and function in low-oxygen culture and during transplantation and are likely to provide more efficient utilisation of islet tissue, a finding of importance for the future of cell therapy for diabetes.
| S-EPMC4327903 | biostudies-literature
Project description:The protein α-actinin-3 expressed in fast-twitch skeletal muscle fiber is absent in 1.5 billion people worldwide due to homozygosity for a nonsense polymorphism in ACTN3 (R577X). The prevalence of the 577X allele increased as modern humans moved to colder climates, suggesting a link between α-actinin-3 deficiency and improved cold tolerance. Here, we show that humans lacking α-actinin-3 (XX) are superior in maintaining core body temperature during cold-water immersion due to changes in skeletal muscle thermogenesis. Muscles of XX individuals displayed a shift toward more slow-twitch isoforms of myosin heavy chain (MyHC) and sarcoplasmic reticulum (SR) proteins, accompanied by altered neuronal muscle activation resulting in increased tone rather than overt shivering. Experiments on Actn3 knockout mice showed no alterations in brown adipose tissue (BAT) properties that could explain the improved cold tolerance in XX individuals. Thus, this study provides a mechanism for the positive selection of the ACTN3 X-allele in cold climates and supports a key thermogenic role of skeletal muscle during cold exposure in humans.
| S-EPMC8008486 | biostudies-literature
Project description:Cold-induced injuries severely limit opportunities and outcomes of hypothermic therapies and organ preservation, calling for better understanding of cold adaptation. Here, by surveying cold-altered chromatin accessibility and integrated CUT&Tag/RNA-seq analyses in human stem cells, we reveal forkhead box O1 (FOXO1) as a key transcription factor for autonomous cold adaptation. Accordingly, we find a nonconventional, temperature-sensitive FOXO1 transport mechanism involving the nuclear pore complex protein RANBP2, SUMO-modification of transporter proteins Importin-7 and Exportin-1, and a SUMO-interacting motif on FOXO1. Our conclusions are supported by cold survival experiments with human cell models and zebrafish larvae. Promoting FOXO1 nuclear entry by the Exportin-1 inhibitor KPT-330 enhances cold tolerance in pre-diabetic obese mice, and greatly prolongs the shelf-life of human and mouse pancreatic tissues and islets. Transplantation of mouse islets cold-stored for 14 days reestablishes normoglycemia in diabetic mice. Our findings uncover a regulatory network and potential therapeutic targets to boost spontaneous cold adaptation.
| S-EPMC10991392 | biostudies-literature
Project description:Islet transplantation can temporarily cure type 1 diabetes mellitus (T1DM) but requires simultaneous immunosuppression to avoid allograft rejection. In this issue of the JCI, Monti et al. report that immune conditioning via use of the Edmonton protocol - a treatment approach in which T1DM patients infused with pancreatic islets from multiple cadaveric donors simultaneously receive immunosuppressive drugs - results in lymphopenia that is associated with elevated serum levels of the homeostatic cytokines IL-7 and IL-15, which causes in vivo expansion of the autoreactive CD8(+) T cell population (see the related article beginning on page 1806). Reemergence of autoreactivity is likely the main culprit underlying long-term islet graft failure, and new strategies will need to be tested to circumvent this homeostatic expansion and recurrent autoreactivity.
| S-EPMC2323197 | biostudies-literature
Project description:To examine if the loss of alpha-actinin-3, a fast skeletal muscle protein, modifies core body temperture following acute cold exposure in humans and a mice Using an Actn3 KO mice model we explore the effects of cold exposure on brown adipose tissue function following exposure to cold (4oC) for 5 hours, compared to control mice housed at either thermoneutrality (30oC) or standard room temperature (22oC)
2021-01-16 | GSE164936 | GEO
Project description:Severe or repeated hypoglycemia events may favor memory complaints in type 1 diabetes (T1D). Pancreatic islet transplantation (IT) is an alternative option to exogenous insulin therapy in case of labile T1D, implying a maintenance immunosuppression regimen based on sirolimus or mycophenolate, associated with tacrolimus, that may also have neurological toxicity. The objective of this study was to compare a cognitive rating scale Mini-Mental State Examination (MMSE) between T1D patients with or without IT and to identify parameters influencing MMSE.MethodsThis retrospective cross-sectional study compared MMSE and cognitive function tests between islet-transplanted T1D patients and nontransplanted T1D controls who were transplant candidates. Patients were excluded if they refused.ResultsForty-three T1D patients were included: 9 T1D patients before IT and 34 islet-transplanted patients (14 treated with mycophenolate and 20 treated with sirolimus). Neither MMSE score (P = 0.70) nor higher cognitive function differed between islet versus non-islet-transplanted patients, whatever the type of immunosuppression. In the whole population (N = 43), MMSE score was negatively correlated to glycated hemoglobin (r = -0.30; P = 0.048) and the time spent in hypoglycemia on the continuous glucose monitoring (r = -0.32; P = 0.041). MMSE score was not correlated to fasting C-peptide level, time spent in hyperglycemia, average blood glucose, time under immunosuppression, duration of diabetes, or beta-score (success score of IT).ConclusionsThis first study evaluating cognitive disorders in islet-transplanted T1D patients argues for the importance of glucose balance on cognitive function rather than of immunosuppressive treatment, with a favorable effect of glucose balance improvement on MMSE score after IT.
| S-EPMC10219717 | biostudies-literature
Project description:We are living exciting times in the field of beta cell replacement therapies for the treatment of diabetes. While steady progress has been recorded thus far in clinical islet transplantation, novel approaches are needed to make cell-based therapies more reproducible and leading to long-lasting success. The multiple facets of diabetes impose the need for a transdisciplinary approach to attain this goal, by targeting immunity, promoting engraftment and sustained functional potency. We discuss herein the emerging technologies applied to this rapidly evolving field.
| S-EPMC4469528 | biostudies-literature
Project description:Diabetes mellitus is a chronic metabolic disease, characterized by high blood sugar levels; it affects more than 500 million individuals worldwide. Type 1 diabetes mellitus (T1DM) is results from insufficient insulin secretion by islets; its treatment requires lifelong use of insulin injections, which leads to a large economic burden on patients. Islet transplantation may be a promising effective treatment for T1DM. Clinically, this process currently involves directly infusing islet cells into the hepatic portal vein; however, transplantation at this site often elicits immediate blood-mediated inflammatory and acute immune responses. Subcutaneous islet transplantation is an attractive alternative to islet transplantation because it is simpler, demonstrates lower surgical complication risks, and enables graft monitoring and removal. In this article, we review the current methods of subcutaneous device-free islet transplantation. Recent subcutaneous islet transplantation techniques with high success rate have involved the use of bioengineering technology and biomaterial cotransplantation-including cell and cell growth factor co-transplantation and hydrogel- or simulated extracellular matrix-wrapped subcutaneous co-transplantation. In general, current subcutaneous device-free islet transplantation modalities can simplify the surgical process and improve the posttransplantation graft survival rate, thus aiding effective T1DM management.
| S-EPMC10642112 | biostudies-literature
Project description:The fast skeletal muscle protein α-actinin-3 is absent in 1.5 billion people worldwide due to homozygosity for a nonsense polymorphism in the ACTN3 gene (R577X). The prevalence of the 577X allele increased as modern humans moved to colder climates, suggesting a link between α-actinin-3 deficiency and improved cold tolerance. Here, we show that humans lacking α-actinin-3 (XX) are superior in maintaining core body temperature during cold-water immersion due to changes in skeletal muscle thermogenesis. Muscles of XX individuals displayed a shift towards more slow-twitch isoforms of myosin heavy chain (MyHC) and sarcoplasmic reticulum (SR) proteins, accompanied by altered neuronal muscle activation resulting in increased tone rather than overt shivering. Experiments on Actn3 knockout mice showed no alterations in brown adipose tissue (BAT) properties that could explain the improved cold tolerance in XX individuals. Thus, this study provides a clear mechanism for the positive selection of the ACTN3 X-allele in cold climates and supports a key thermogenic role of skeletal muscle during cold exposure in humans.
2021-03-16 | PXD022997 | Pride