scholarly journals Immune Protection of Stem Cell-Derived Islet Cell Therapy for Treating Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Meghan Tahbaz ◽  
Eiji Yoshihara
Keyword(s):  
Stem Cell ◽  
Cell Therapy ◽  
Pancreatic Islets ◽  
Immune Tolerance ◽  
Islet Cell ◽  
Human Islets ◽  
Immune Protection ◽  
Pancreatic Islet Transplantation ◽  
Human Pancreatic Islets ◽  
Increased Risk

Insulin injection is currently the main therapy for type 1 diabetes (T1D) or late stage of severe type 2 diabetes (T2D). Human pancreatic islet transplantation confers a significant improvement in glycemic control and prevents life-threatening severe hypoglycemia in T1D patients. However, the shortage of cadaveric human islets limits their therapeutic potential. In addition, chronic immunosuppression, which is required to avoid rejection of transplanted islets, is associated with severe complications, such as an increased risk of malignancies and infections. Thus, there is a significant need for novel approaches to the large-scale generation of functional human islets protected from autoimmune rejection in order to ensure durable graft acceptance without immunosuppression. An important step in addressing this need is to strengthen our understanding of transplant immune tolerance mechanisms for both graft rejection and autoimmune rejection. Engineering of functional human pancreatic islets that can avoid attacks from host immune cells would provide an alternative safe resource for transplantation therapy. Human pluripotent stem cells (hPSCs) offer a potentially limitless supply of cells because of their self-renewal ability and pluripotency. Therefore, studying immune tolerance induction in hPSC-derived human pancreatic islets will directly contribute toward the goal of generating a functional cure for insulin-dependent diabetes. In this review, we will discuss the current progress in the immune protection of stem cell-derived islet cell therapy for treating diabetes.

Multilayer Nanoencapsulation. New Approach for Immune Protection of Human Pancreatic Islets

Nano Letters ◽  
2006 ◽  
Vol 6 (9) ◽  
pp. 1933-1939 ◽  
Author(s):  
Silke Krol ◽  
Silvia del Guerra ◽  
Maria Grupillo ◽  
Alberto Diaspro ◽  
Alessandra Gliozzi ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Immune Protection ◽  
New Approach ◽  
Human Pancreatic Islets

Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPARγ2 in the modulation of insulin secretion

2004 ◽  
Vol 286 (4) ◽  
pp. E560-E567 ◽  
Author(s):  
R. Lupi ◽  
S. Del Guerra ◽  
L. Marselli ◽  
M. Bugliani ◽  
U. Boggi ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Mrna Expression ◽  
Pancreatic Islets ◽  
Human Islets ◽  
Acid Mixture ◽  
Human Pancreatic Islets ◽  
Pparγ Agonist ◽  
Pparγ Agonists ◽  
Insulin Mrna

Peroxisome proliferator-activated receptors (PPARs) are a subgroup of the superfamily of nuclear receptors, with three distinct main types: α, β and γ (subdivided into γ1 and γ2). Recently, the presence of PPARγ has been reported in human islets. Whether other PPAR types can be found in human islets, how islet PPARγ mRNA expression is regulated by the metabolic milieu, their role in insulin secretion, and the effects of a PPARγ agonist are not known. In this study, human pancreatic islets were prepared by collagenase digestion and density gradient purification from nonobese adult donors. The presence of PPAR mRNAs was assessed by RT-PCR, and the effect was evaluated of exposure for up to 24 h to either 22.2 mmol/l glucose and/or 0.25, 0.5, or 1.0 mmol/l long-chain fatty acid mixture (oleate to palmitate, 2:1). PPARβ and, to a greater extent, total PPARγ and PPARγ2 mRNAs were expressed in human islets, whereas PPARα mRNA was not detected. Compared with human adipose tissue, PPARγ mRNA was expressed at lower levels in the islets, and PPARβ at similar levels. The expression of PPARγ2 mRNA was not affected by exposure to 22.2 mmol/l glucose, whereas it decreased markedly and time dependently after exposure to progressively higher free fatty acids (FFA). This latter effect was not affected by the concomitant presence of high glucose. Exposure to FFA caused inhibition of insulin mRNA expression, glucose-stimulated insulin release, and reduction of islet insulin content. The PPARγ agonists rosiglitazone and 15-deoxy-Δ-12,14prostaglandin J2 prevented the cytostatic effect of FFA as well as the FFA-induced changes of PPAR and insulin mRNA expression. In conclusion, this study shows that PPARγ mRNA is expressed in human pancreatic islets, with predominance of PPARγ2; exposure to FFA downregulates PPARγ2 and insulin mRNA expression and inhibits glucose-stimulated insulin secretion; exposure to PPARγ agonists can prevent these effects.

scholarly journals Evaluation of Multi-Layered Pancreatic Islets and Adipose-Derived Stem Cell Sheets Transplanted on Various Sites for Diabetes Treatment

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1999
Author(s):  
Yu Na Lee ◽  
Hye-Jin Yi ◽  
Yang Hee Kim ◽  
Song Lee ◽  
Jooyun Oh ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Transplantation ◽  
Graft Survival ◽  
Glucose Control ◽  
Islet Cell ◽  
Human Islets ◽  
Islet Cell Transplantation ◽  
Cell Sheets ◽  
Peritoneal Surface

Islet cell transplantation is considered an ideal treatment for insulin-deficient diabetes, but implantation sites are limited and show low graft survival. Cell sheet technology and adipose-derived stem cells (ADSCs) can be useful tools for improving islet cell transplantation outcomes since both can increase implantation efficacy and graft survival. Herein, the optimal transplantation site in diabetic mice was investigated using islets and stem cell sheets. We constructed multi-layered cell sheets using rat/human islets and human ADSCs. Cell sheets were fabricated using temperature-responsive culture dishes. Islet/ADSC sheet (AI sheet) group showed higher viability and glucose-stimulated insulin secretion than islet-only group. Compared to islet transplantation alone, subcutaneous AI sheet transplantation showed better blood glucose control and CD31+ vascular traits. Because of the adhesive properties of cell sheets, AI sheets were easily applied on liver and peritoneal surfaces. Liver or peritoneal surface grafts showed better glucose control, weight gain, and intraperitoneal glucose tolerance test (IPGTT) profiles than subcutaneous site grafts using both rat and human islets. Stem cell sheets increased the therapeutic efficacy of islets in vivo because mesenchymal stem cells enhance islet function and induce neovascularization around transplanted islets. The liver and peritoneal surface can be used more effectively than the subcutaneous site in future clinical applications.

scholarly journals Persistent Infection of Human Pancreatic Islets by Coxsackievirus B Is Associated with Alpha Interferon Synthesis in β Cells

2000 ◽  
Vol 74 (21) ◽  
pp. 10153-10164 ◽  
Author(s):  
Wassim Chehadeh ◽  
Julie Kerr-Conte ◽  
François Pattou ◽  
Gunar Alm ◽  
Jean Lefebvre ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Islet Cells ◽  
Human Islets ◽  
Adult Brain ◽  
Viral Rna ◽  
Alpha Interferon ◽  
Β Cells ◽  
Human Pancreatic Islets ◽  
Reverse Transcription Pcr ◽  
Vp1 Capsid Protein

ABSTRACT The interactions of coxsackievirus B3 (CVB3), CVB4E2 (diabetogenic), and CVB4JBV (nondiabetogenic) strains with human pancreatic islets from eight adult brain-dead donors were investigated. Persistent replication of viruses in human islets was proved by detection of viral RNA by in situ hybridization, VP1 capsid protein by immunofluorescence (IF) staining, negative-strand viral RNA by reverse transcription-PCR in extracted RNA from islets, and release of infectious particles up to 30 days after infection without obvious cytolysis. By double IF staining, glucagon-containing α cells and insulin-containing β cells were shown to be susceptible to CVB. The persistence of CVB3 and CVB4 in islet cells was associated with the chronic synthesis of alpha interferon (IFN-α), as evidenced by the detection of IFN-α mRNA and immunoreactive IFN-α with antiviral activity. By double IF staining, IFN-α was detected in insulin-producing β cells only. Experiments with neutralizing anti-coxsackievirus and adenovirus receptor (CAR) antibodies provided evidence that CAR was expressed by α and β cells and that it played a role in the infection of these cells with CVB and the consecutive IFN-α expression in β cells. The viral replication and the expression of IFN-α in islets were not restricted to the CVB4E2 diabetogenic strain and did not depend on the genetic background of the host. The neutralization of endogenous IFN-α significantly enhanced the CVB replication in islet cells and resulted in rapid destruction of islets. Thus, human β cells can harbor a persistent CVB infection, and CVB-induced IFN-α plays a role in the initiation and/or maintenance of chronic CVB infection in human islets.

scholarly journals Asymmetrical distribution of δ and PP cells in human pancreatic islets

2016 ◽  
Vol 229 (2) ◽  
pp. 123-132 ◽  
Author(s):  
Charlotte Barbieux ◽  
Géraldine Parnaud ◽  
Vanessa Lavallard ◽  
Estelle Brioudes ◽  
Jérémy Meyer ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pancreatic Islets ◽  
Islet Cells ◽  
Human Islets ◽  
Human Pancreatic Islets ◽  
Asymmetrical Distribution ◽  
Computerized Morphometry ◽  
Vascular Channels ◽  
Type 2 Diabetic

The aim of this study was to evaluate the location of PP and δ cells in relation to the vascularization within human pancreatic islets. To this end, pancreas sections were analysed by immunofluorescence using antibodies against endocrine islet and endothelial cells. Staining in different islet areas corresponding to islet cells adjacent or not to peripheral or central vascular channels was quantified by computerized morphometry. As results, α, PP and δ cells were preferentially found adjacent to vessels. In contrast to α cells, which were evenly distributed between islet periphery and intraislet vascular channels, PP and δ cells had asymmetric and opposite distributions: PP staining was higher and somatostatin staining was lower in the islet periphery than in the area around intraislet vascular channels. Additionally, frequencies of PP and δ cells were negatively correlated in the islets. No difference was observed between islets from the head and the tail of the pancreas, and from type 2 diabetic and non-diabetic donors. In conclusion, the distribution of δ cells differs from that of PP cells in human islets, suggesting that vessels at the periphery and at the centre of islets drain different hormonal cocktails.

scholarly journals Expression Profile of SARS-CoV-2 Host Receptors in Human Pancreatic Islets Revealed Upregulation of ACE2 in Diabetic Donors

Biology ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 215 ◽  
Author(s):  
Jalal Taneera ◽  
Waseem El-Huneidi ◽  
Mawieh Hamad ◽  
Abdul Khader Mohammed ◽  
Esraa Elaraby ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Endocrine Cells ◽  
Human Islets ◽  
Diabetic Patients ◽  
Rna Seq ◽  
Human Pancreatic Islets ◽  
Diabetes Status ◽  
Subcutaneous Adipose ◽  
Type 2 Diabetic

Cellular entry of SARS-CoV-2 is thought to occur through the binding of viral spike S1 protein to ACE2. The entry process involves priming of the S protein by TMPRSS2 and ADAM17, which collectively mediate the binding and promote ACE2 shedding. In this study, microarray and RNA-sequencing (RNA-seq) expression data were utilized to profile the expression pattern of ACE2, ADAM17, and TMPRSS2 in type 2 diabetic (T2D) and non-diabetic human pancreatic islets. Our data show that pancreatic islets express all three receptors irrespective of diabetes status. The expression of ACE2 was significantly increased in diabetic/hyperglycemic islets compared to non-diabetic/normoglycemic. Islets from female donors showed higher ACE2 expression compared to males; the expression of ADAM17 and TMPRSS2 was not affected by gender. The expression of the three receptors was statistically similar in young (≤40 years old) versus old (≥60 years old) donors. Obese (BMI > 30) donors have significantly higher expression levels of ADAM17 and TMPRSS2 relative to those from non-obese donors (BMI < 25). TMPRSS2 expression correlated positively with HbA1c and negatively with age, while ADAM17 and TMPRSS2 correlated positively with BMI. The expression of the three receptors was statistically similar in muscle and subcutaneous adipose tissues obtained from diabetic and nondiabetic donors. Lastly, ACE2 expression was higher in sorted pancreatic β-cell relative to other endocrine cells. In conclusion, ACE2 expression is increased in diabetic human islets. More studies are required to investigate whether variations of ACE2 expression could explain the severity of COVID-19 infection-related symptoms between diabetics and non-diabetic patients.

scholarly journals Ex vivo transcriptional profiling of human pancreatic islets following chronic exposure to monounsaturated fatty acids

2007 ◽  
Vol 196 (3) ◽  
pp. 455-464 ◽  
Author(s):  
George Bikopoulos ◽  
Aurelio da Silva Pimenta ◽  
Simon C Lee ◽  
Jonathan R Lakey ◽  
Sandy D Der ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Pancreatic Islets ◽  
Chronic Exposure ◽  
Ex Vivo ◽  
Transcriptional Profiling ◽  
Gene Clusters ◽  
Human Islets ◽  
Insulin Content ◽  
Ros Generation ◽  
Human Pancreatic Islets

The aim of this study was to assess the effects of chronic free fatty acid (FFA) exposure on gene expression and the functional state of human pancreatic islets. Chronic exposure of islets to oleate (OA) resulted in a significant reduction in glucose-stimulated insulin secretion (GSIS) compared with control (466±82 vs 234±57 ng/μg DNA, P<0.05). OA treatment also led to reduction in total insulin content of the islets (17 609±3816 vs 10 599±3876 ng insulin/μg DNA) and to an increase in the rate of reactive oxygen species (ROS) generation. Interestingly, the suppressive effects of OA on biosynthesis and secretion of insulin were accompanied by alteration in the expression of 40 genes, as determined by microarray analysis and subsequent qPCR validation. The majority of genes regulated by OA encoded metabolic enzymes. The expression of enzymes involved in oxidative defense was elevated, indicating a link between ROS generation and antioxidant defense activation. Additionally, pretreatment of human islets with OA led to a significant increase (30%) in the rate of oxidation of this fatty acid and to a significant decrease (75%) in glucose oxidation. Importantly, individual analysis of gene clusters from the islets of all donors revealed the induction of genes involved in inflammation and immunity, which provides further evidence that FFA are risk factors for the development of type 2 diabetes. In summary, our data indicate that chronic exposure of human islets to FFA activates inflammatory and metabolic pathways that lead to oxidative stress, reduced β-cell insulin content, and inhibition of GSIS.

scholarly journals Using single-nucleus RNA-sequencing to interrogate transcriptomic profiles of archived human pancreatic islets

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Giorgio Basile ◽  
Sevim Kahraman ◽  
Ercument Dirice ◽  
Hui Pan ◽  
Jonathan M. Dreyfuss ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Rna Sequencing ◽  
Islet Cells ◽  
Strong Association ◽  
Cell Types ◽  
Human Islets ◽  
Human Islet ◽  
Human Pancreatic Islets ◽  
Single Nucleus ◽  
Type Gene

Abstract Background Human pancreatic islets are a central focus of research in metabolic studies. Transcriptomics is frequently used to interrogate alterations in cultured human islet cells using single-cell RNA-sequencing (scRNA-seq). We introduce single-nucleus RNA-sequencing (snRNA-seq) as an alternative approach for investigating transplanted human islets. Methods The Nuclei EZ protocol was used to obtain nuclear preparations from fresh and frozen human islet cells. Such preparations were first used to generate snRNA-seq datasets and compared to scRNA-seq output obtained from cells from the same donor. Finally, we employed snRNA-seq to obtain the transcriptomic profile of archived human islets engrafted in immunodeficient animals. Results We observed virtually complete concordance in identifying cell types and gene proportions as well as a strong association of global and islet cell type gene signatures between scRNA-seq and snRNA-seq applied to fresh and frozen cultured or transplanted human islet samples. Conclusions We propose snRNA-seq as a reliable strategy to probe transcriptomic profiles of freshly harvested or frozen sources of transplanted human islet cells especially when scRNA-seq is not ideal.

scholarly journals Atorvastatin but Not Pravastatin Impairs Mitochondrial Function in Human Pancreatic Islets and Rat β-Cells. Direct Effect of Oxidative Stress

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Francesca Urbano ◽  
Marco Bugliani ◽  
Agnese Filippello ◽  
Alessandra Scamporrino ◽  
Stefania Di Mauro ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pancreatic Islets ◽  
Cell Function ◽  
Antioxidant Defense System ◽  
Design Strategies ◽  
Β Cell ◽  
Mitochondrial Oxidative Stress ◽  
Human Pancreatic Islets ◽  
Increased Risk ◽  
Β Cell Function

AbstractStatins are a class of drugs widely prescribed as frontline therapy for lowering plasma LDL-cholesterol in cardiovascular risk prevention. Several clinical reports have recently suggested an increased risk of type 2 diabetes associated with chronic use of these drugs. The pathophysiology of this effect remains to be fully elucidated but impaired β-cell function constitutes a potential mechanism. The aim of this study was to explore the effect of a chronic treatment with lipophilic and hydrophilic statins on β-cell function, using human pancreatic islets and rat insulin-secreting INS-1 cells; we particularly focused on the role of mitochondria and oxidative stress. The present study demonstrates, for the first time, that atorvastatin (lipophilic) but not pravastatin (hydrophilic) affected insulin release and mitochondrial metabolism due to the suppression of antioxidant defense system and induction of ROS production in pancreatic β-cell models. Mevalonate addition and treatment with a specific antioxidant (N-AcetylCysteine) effectively reversed the observed defects. These data demonstrate that mitochondrial oxidative stress is a key element in the pathogenesis of statin-related diabetes and may have clinical relevance to design strategies for prevention or reduction of statin induced β-cell dysfunction and diabetes in patients treated with lipophilic statins.

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