TREATMENT WITH ANAKINRA AND TOCILIZUMAB REDUCE THE PRO-INFLAMMATORY RESPONSE AND ENHANCES ISLET SURVIVAL AND FUNCTION IN HUMAN ISLETS DURING CULTURE: IMPLICATIONS FOR CLINICAL ISLET TRANSPLANTATION.

2010 ◽  
Vol 90 ◽  
pp. 373
Author(s):  
A. Sahraoui ◽  
K. Kloster-Jensen ◽  
T. Lund ◽  
O. Korsgren ◽  
A. Foss ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Islet Transplantation ◽  
Human Islets ◽  
Clinical Islet Transplantation ◽  
And Function ◽  
Islet Survival

scholarly journals Beta-cell function and human islet transplantation: can we improve?

2021 ◽  
Author(s):  
Jennifer Chen ◽  
Jenny E Gunton
Keyword(s):  
Islet Transplantation ◽  
Cell Function ◽  
Therapeutic Option ◽  
Human Islets ◽  
Post Transplantation ◽  
Human Islet Transplantation ◽  
And Function ◽  
Islet Survival

Islet transplantation, a therapeutic option to treat type 1 diabetes, is not yet as successful as whole-pancreas transplantation as a treatment for diabetes. Mouse models are commonly used for islet research. However, it is clear disparities exist between islet transplantation outcomes in mice and humans. Given the shortage of transplant-grade islets, it is crucial that we further our understanding of factors that determine long-term islet survival and function post-transplantation. In turn, that may lead to new therapeutic targets and strategies that to improve transplant outcomes. Here, we summarise the current landscape in clinical transplantation, highlight underlying similarities and differences between mouse and human islets, and review interventions that are being considered to create a new pool of β-cells for clinical application.

scholarly journals Hypoxia-Preconditioned Wharton’s Jelly-Derived Mesenchymal Stem Cells Mitigate Stress-Induced Apoptosis and Ameliorate Human Islet Survival and Function in Direct Contact Coculture System

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Somayeh Keshtkar ◽  
Maryam Kaviani ◽  
Zahra Jabbarpour ◽  
Fatemeh Sabet Sarvestani ◽  
Mohammad Hossein Ghahremani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Human Islets ◽  
Wharton’S Jelly ◽  
Isolated Pancreatic Islets ◽  
Wharton's Jelly ◽  
Coculture System ◽  
Induced Apoptosis ◽  
And Function ◽  
Islet Survival

Protection of isolated pancreatic islets against hypoxic and oxidative damage-induced apoptosis is essential during a pretransplantation culture period. A beneficial approach to maintain viable and functional islets is the coculture period with mesenchymal stem cells (MSCs). Hypoxia preconditioning of MSCs (Hpc-MSCs) for a short time stimulates the expression and secretion of antiapoptotic, antioxidant, and prosurvival factors. The aim of the present study was to evaluate the survival and function of human islets cocultured with Hpc-MSCs. Wharton’s jelly-derived MSCs were subjected to hypoxia (5% O2: Hpc) or normoxia (20% O2: Nc) for 24 hours and then cocultured with isolated human islets in direct and indirect systems. Assays of viability and apoptosis, along with the production of reactive oxygen species (ROS), hypoxia-inducible factor 1-alpha (HIF-1α), apoptotic pathway markers, and vascular endothelial growth factor (VEGF) in the islets, were performed. Insulin and C-peptide secretions as islet function were also evaluated. Hpc-MSCs and Nc-MSCs significantly reduced the ROS production and HIF-1α protein aggregation, as well as downregulation of proapoptotic proteins and upregulation of antiapoptotic marker along with increment of VEGF secretion in the cocultured islet. However, the Hpc-MSCs groups were better than Nc-MSCs cocultured islets. Hpc-MSCs in both direct and indirect coculture systems improved the islet survival, while promotion of function was only significant in the direct cocultured cells. Hpc potentiated the cytoprotective and insulinotropic effects of MSCs on human islets through reducing stressful markers, inhibiting apoptosis pathway, enhancing prosurvival factors, and promoting insulin secretion, especially in direct coculture system, suggesting the effective strategy to ameliorate the islet quality for better transplantation outcomes.

scholarly journals Extra-Hepatic Islet Transplantation

2018 ◽  
Vol 27 (8) ◽  
pp. 1289-1293 ◽  
Author(s):  
Anaïs Schaschkow ◽  
Séverine Sigrist ◽  
Carole Mura ◽  
Caroline Dissaux ◽  
Karim Bouzakri ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Cell Therapy ◽  
Islet Transplantation ◽  
Graft Function ◽  
Surgical Techniques ◽  
Diabetic Rats ◽  
C Peptide ◽  
And Function ◽  
Islet Survival

Following the tremendous development of hydrogels for cell therapy, there is now a growing need for surgical techniques to validate in vivo scaffold benefits for islet transplantation. Therefore, we propose a newly designed surgical procedure involving the injection of hydrogel-embedded pancreatic islets in the omentum, which is considered a favorable environment for cell survival and function. Our technique, called h-Omental Matrix Islet filliNG (hOMING) was designed to test the benefits of hydrogel on islet survival and function in vivo. Islets were implanted in the omentum of diabetic rats using the hOMING technique and alginate as an islet carrier. Blood glucose and C-peptide levels were recorded to assess graft function. After 2 months, grafts were explanted and studied using insulin and vessel staining. All rats that underwent hOMING exhibited graft function characterized by a glycemia decrease and a C-peptidemia increase ( P < 0.001 compared with preoperative levels). Furthermore, hOMING appeared to preserve islet morphology and insulin content and allowed the proper revascularization of grafted islets. The results suggest that hOMING is a viable and promising approach to test in vivo the benefits of hydrogel administration for islet transplantation into the omental tissue.

scholarly journals IGF2: an endocrine hormone to improve islet transplant survival

2014 ◽  
Vol 221 (2) ◽  
pp. R41-R48 ◽  
Author(s):  
Amy Hughes ◽  
Darling Rojas-Canales ◽  
Chris Drogemuller ◽  
Nicolas H Voelcker ◽  
Shane T Grey ◽  
...  
Keyword(s):  
Cell Death ◽  
Islet Transplantation ◽  
Inflammatory Cytokine ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Pancreatic Islet Transplantation ◽  
Post Transplant ◽  
Islet Transplant ◽  
Clinical Islet Transplantation ◽  
Islet Survival

In the week following pancreatic islet transplantation, up to 50% of transplanted islets are lost due to apoptotic cell death triggered by hypoxic and pro-inflammatory cytokine-mediated cell stress. Thus, therapeutic approaches designed to protect islet cells from apoptosis could significantly improve islet transplant success. IGF2 is an anti-apoptotic endocrine protein that inhibits apoptotic cell death through the mitochondrial (intrinsic pathway) or via antagonising activation of pro-inflammatory cytokine signalling (extrinsic pathway), in doing so IGF2 has emerged as a promising therapeutic molecule to improve islet survival in the immediate post-transplant period. The development of novel biomaterials coated with IGF2 is a promising strategy to achieve this. This review examines the mechanisms mediating islet cell apoptosis in the peri- and post-transplant period and aims to identify the utility of IGF2 to promote islet survival and enhance long-term insulin independence rates within the setting of clinical islet transplantation.

scholarly journals Allogeneic Bone Marrow Cocultured With Human Islets Significantly Improves Islet Survival and Function In Vivo

2013 ◽  
Vol 95 (6) ◽  
pp. 801-809 ◽  
Author(s):  
John Z.Q. Luo ◽  
Fang Xiong ◽  
A. Samer Al-Homsi ◽  
Camillo Ricordi ◽  
LuGuang Luo
Keyword(s):  
Bone Marrow ◽  
Human Islets ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
And Function ◽  
Islet Survival

scholarly journals Calcium

2018 ◽  
Vol 27 (7) ◽  
pp. 1031-1038 ◽  
Author(s):  
Torsten Eich ◽  
Magnus Ståhle ◽  
Bengt Gustafsson ◽  
Rune Horneland ◽  
Marko Lempinen ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Islet Transplantation ◽  
Clinical Chemistry ◽  
Pancreatic Enzyme ◽  
Human Islets ◽  
Human Pancreas ◽  
Islet Isolation ◽  
Clinical Islet Transplantation ◽  
The Media ◽  
Major Reduction

Background: Effective digestive enzymes are crucial for successful islet isolation. Supplemental proteases are essential because they synergize with collagenase for effective pancreatic digestion. The activity of these enzymes is critically dependent on the presence of Ca2+ ions at a concentration of 5–10 mM. The present study aimed to determine the Ca2+ concentration during human islet isolation and to ascertain whether the addition of supplementary Ca2+ is required to maintain an optimal Ca2+ concentration during the various phases of the islet isolation process. Methods: Human islets were isolated according to standard methods and isolation parameters. Islet quality control and the number of isolations fulfilling standard transplantation criteria were evaluated. Ca2+ was determined by using standard clinical chemistry routines. Islet isolation was performed with or without addition of supplementary Ca2+ to reach a Ca2+ of 5 mM. Results: Ca2+ concentration was markedly reduced in bicarbonate-based buffers, especially if additional bicarbonate was used to adjust the pH as recommended by the Clinical Islet Transplantation Consortium. A major reduction in Ca2+ concentration was also observed during pancreatic enzyme perfusion, digestion, and harvest. Additional Ca2+ supplementation of media used for dissolving the enzymes and during digestion, perfusion, and harvest was necessary in order to obtain the concentration recommended for optimal enzyme activity and efficient liberation of a large number of islets from the human pancreas. Conclusions: Ca2+ is to a large extent consumed during clinical islet isolation, and in the absence of supplementation, the concentration fell below that recommended for optimal enzyme activity. Ca2+ supplementation of the media used during human pancreas digestion is necessary to maintain the concentration recommended for optimal enzyme activity. Addition of Ca2+ to the enzyme blend has been implemented in the standard isolation protocols in the Nordic Network for Clinical Islet Transplantation.

scholarly journals Anakinra and Tocilizumab Enhance Survival and Function of Human Islets during Culture: Implications for Clinical Islet Transplantation

2014 ◽  
Vol 23 (10) ◽  
pp. 1199-1211 ◽  
Author(s):  
Afaf Sahraoui ◽  
Kristine Kloster-Jensen ◽  
Thor Ueland ◽  
Olle Korsgren ◽  
Aksel Foss ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
Glycosylated Hemoglobin ◽  
Human Islets ◽  
Diabetic Patients ◽  
Β Cells ◽  
Mass Model ◽  
Immunodeficient Mice ◽  
Markers Of Inflammation ◽  
Clinical Islet Transplantation ◽  
The Impact

Pretreatment culture before islet transplantation represents a window of opportunity to ameliorate the pro-inflammatory profile expressed by human β-cells in duress. Anakinra (IL-1 receptor antagonist) and tocilizumab (monoclonal IL-6 receptor antibody) are two known anti-inflammatory agents successfully used in the treatment of inflammatory states like rheumatoid arthritis. Both compounds have also been shown to reduce blood glucose and glycosylated hemoglobin in diabetic patients. We therefore sought to evaluate the impact of anakinra and tocilizumab on human β-cells. The islets were precultured with or without anakinra or tocilizumab and then transplanted in a marginal mass model using human islets in immunodeficient mice. Islet viability was evaluated in an in vitro model. The pretreatment culture led to a significantly improved engraftment in treated islets compared to the vehicle. Anakinra and tocilizumab are not toxic to human islets and significantly reduce markers of inflammation and cell death. These results strongly support a pretreatment culture with anakinra and tocilizumab prior to human islet transplantation.

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