Pancreatic islet transplantation under the kidney capsule of mice: model of refinement for molecular and ex-vivo graft analysis

2021 ◽  
pp. 002367722110040
Author(s):  
Julien Thévenet ◽  
Valery Gmyr ◽  
Nathalie Delalleau ◽  
François Pattou ◽  
Julie Kerr-Conte
Keyword(s):  
Islet Transplantation ◽  
Pain Treatment ◽  
Ex Vivo ◽  
Well Being ◽  
Diabetic Patients ◽  
Mice Model ◽  
Pancreatic Islet Transplantation ◽  
Post Transplantation ◽  
Kidney Capsule

Diabetes cell therapy by human islet transplantation can restore an endogenous insulin secretion and normal glycaemic control in type 1 diabetic patients for as long as 10 years post transplantation. Before transplantation, each clinical islet preparation undergoes extensive in-vitro and in-vivo quality controls. The in-vivo quality control assay consists of transplanting human islets under the kidney capsule of immunocompromised mice. Currently, it is considered the best predictive factor to qualify clinical transplant efficiency. This chimeric model offers a wide area of study since it combines the possibility of producing not only quantitative but also a maximum of qualitative data. Today’s technological advances allow us to obtain more accurate and stronger data from the animals used in research while ensuring their comfort and well-being throughout the protocol, including cage enrichment and pain treatment during and after surgery. As demonstrated in this valuable model, we are able to generate more usable results (Refine), while reducing the number of animals used (Reduce), by focusing on the development of ex-vivo analysis techniques (Replace), which clearly highlights the Burch and Russell 3Rs concept.

scholarly journals THERAPY OF ENDOCRINE DISEASE: Islet transplantation for type 1 diabetes: so close and yet so far away

2015 ◽  
Vol 173 (5) ◽  
pp. R165-R183 ◽  
Author(s):  
Mohsen Khosravi-Maharlooei ◽  
Ensiyeh Hajizadeh-Saffar ◽  
Yaser Tahamtani ◽  
Mohsen Basiri ◽  
Leila Montazeri ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Islet Transplantation ◽  
Diabetic Patients ◽  
Immune Rejection ◽  
Pancreatic Islet Transplantation ◽  
Insulin Independence ◽  
Endocrine Disease ◽  
The Past ◽  
Source Limitation

Over the past decades, tremendous efforts have been made to establish pancreatic islet transplantation as a standard therapy for type 1 diabetes. Recent advances in islet transplantation have resulted in steady improvements in the 5-year insulin independence rates for diabetic patients. Here we review the key challenges encountered in the islet transplantation field which include islet source limitation, sub-optimal engraftment of islets, lack of oxygen and blood supply for transplanted islets, and immune rejection of islets. Additionally, we discuss possible solutions for these challenges.

scholarly journals Subcutaneous Transplantation of Islets into Streptozocin-Induced Diabetic Rats

2005 ◽  
Vol 14 (8) ◽  
pp. 595-605 ◽  
Author(s):  
Craig R. Halberstadt ◽  
Deana Williams ◽  
Dwaine Emerich ◽  
Moses Goddard ◽  
Alfred V. Vasconcellos ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
Cell Function ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Pancreatic Islet Transplantation ◽  
Minimally Invasive Surgical Procedure ◽  
Minimally Invasive Surgical ◽  
Ease Of Access ◽  
Syngeneic Islet Transplantation ◽  
Type 1 Diabetic Patients

Pancreatic islet transplantation into type 1 diabetic patients is currently being performed by intraportal infusion. This method, albeit reproducible, has some disadvantages including potential development of portal hypertension, hemorrhage, and an inability to retrieve or detect the transplanted tissue. Other transplant sites have been examined in animal models including the omentum, peritoneal cavity, and the spleen. A transplant site that has not been successful in supporting functional islet tissue transplantation in humans is the subcutaneous space due primarily to the lack of a well-defined vascular bed. This site has many favorable characteristics such as ease of access for transplantation and potential for removal of the transplanted tissue with a minimally invasive surgical procedure. This report addresses the evaluation of a subcutaneously placed device for the support of rat syngeneic islet transplantation in a streptozocin-induced diabetic model. The data generated support the use of this device for islet engraftment. In addition, beta cell function in this device compared favorably with the function of islets transplanted to the renal subcapsular space as well as islets within the native pancreas.

Nicotinamide, a Recognized Inhibitor of SIRT1, Promotes Expansion in Ex Vivo Cultures of Short and Long-Term Repopulating Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2431-2431 ◽  
Author(s):  
Tony Peled ◽  
Hadas Shoham ◽  
Dorit Aschengrau ◽  
Dima Yackoubov ◽  
Gabi Frei ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Cultured Cells ◽  
Ex Vivo ◽  
Donor Cell ◽  
Mice Model ◽  
Short Term ◽  
Post Transplantation ◽  
Short And Long Term ◽  
Cells Cultured

Abstract Abstract 2431 Poster Board II-408 Nicotinamide (NAM), is a form of VitB3 that recognized and inhibits SIRT1, the human ortholog of the yeast Sir2 class III NAD+-dependent histone deacetylase. We have previously demonstrated that NAM inhibits in vitro differentiation and enhances expansion, migration, homing and NOD/SCID engraftment efficacy of cord blood (CB)-derived CD34+ cells cultured with cytokines. In the current study, the in vivo function of ex vivo cultured cells with NAM was tested in a congenic mice model (BALB/C, CD45.1/CD45.2) for BM transplantation. Purified CD117+ BM cells from BALB/C CD45.1 mice were cultured with a combination of 4 cytokines (FLT3, SCF, TPO, IL-6, 50 ng/ml each), with and without 0.5mM NAM for three weeks. Numbers of CFUc, CD117+ and CD117+Lin- cells were significantly (p < 0.05) higher in cultures treated with NAM as compared with cultured treated with cytokines alone. Non-cultured, freshly purified CD117+ cells (1000 and 2500 cells/mice) and their total progeny following expansion with or without NAM were transplanted into ablated (1000 Rad) CD45.2 mice (n = 10/cohort), 24h post irradiation (Fig 1). Three months post transplantation, all the mice in the control group (non-transplanted) died. The percent survival of mice transplanted with cells cultured with cytokines and NAM was remarkably higher over the survival of mice in the cohort transplanted with cells cultured with cytokines alone or non-cultured cells (Fig 1). FACS analysis (CD45.1-donor / CD45.2-host) of peripheral blood from mice transplanted with NAM cultured cells show 80% donor cell chimerism (CD45.1), 3 and 6 months post transplantation. Percent of donor derived Gr-1+ and CD3+ cells were similar in mice transplanted with non-cultured or NAM cultured cells. Percentages of donor cell chimerism (CD45.1) in secondary mice transplanted with total BM cells derived from primary recipients originally transplanted with non-cultured and NAM cultured cells were 47 and 73, respectively, 6 weeks after the secondary transplantation. In a different experiment, to follow time to engraftment during the first month post transplantation, mice transplanted with non-cultured cells or cells cultured with cytokines and NAM (n = 10/cohort) were bled at weekly intervals and peripheral blood samples were counted for WBC and analyzed by the FACS to determine donor cell chimerism and lineage engraftment. The results show accelerated engraftment (Fig 2) and higher levels of donor cell chimerism (Fig 3) in the cohort transplanted with NAM cultured cells relative to the cohort transplanted with non-cultured cells. Number of granulocytes, T, NK and B cells during the first month post transplant were also significantly (p<0.05) higher in mice transplanted with cells cultured with cytokines and NAM relative to their levels in mice transplanted with non-cultured cells. The results obtained in the congenic mice model for BMT suggest that NAM promotes expansion in ex vivo cultures of short and long-term repopulating cells, as demonstrated by accelerated donor derived engraftment during the first month post transplantation, higher survival of mice, sustained donor cell chimerism 6 month post transplantation and successful reconstitution of secondary recipients. NAM is thus a novel molecule that may be used to stimulate and expand hematopoietic repopulating cells, fasten post transplant engraftment and hopefully improve transplantation outcome. Current studies are designed to elucidate NAM mode of action. Fig 1: Three month survival Fig 1:. Three month survival Fig 2: Short-term Engrafoment Fig: 3 Percentage of Donor Chimerism Fig 2:. Short-term Engrafoment Fig: 3 Percentage of Donor Chimerism Disclosures: Peled: Gamida-Cell: Employment, Equity Ownership. Shoham:Gamida Cell: Employment. Aschengrau:Gamida Cell: Employment. Yackoubov:Gamida Cell: Employment. Frei:Gamida Cell: Employment. Nagler:Gamida Cell: Arnon Nagler, Consultancy. Peled:Gamida Cell: Consultancy.

scholarly journals Pancreas Procurement and Preservation for Islet Transplantation: Personal Considerations

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Hirofumi Noguchi
Keyword(s):  
Islet Transplantation ◽  
Cooling System ◽  
Pancreatic Tissue ◽  
Diabetic Patients ◽  
Pancreatic Islet Transplantation ◽  
Ischemic Time ◽  
Trypsin Inhibition ◽  
Edmonton Protocol ◽  
Collagenase Inhibition ◽  
Type 1 Diabetic Patients

Pancreatic islet transplantation is a promising option for the treatment of type 1 diabetic patients. After the successful demonstration of the Edmonton protocol, islet transplantation has advanced significantly on several fronts, including improved pancreas procurement and preservation systems. Since we frequently use pancreata from donors after cardiac death in Japan,we have applied thein situregional organ cooling system for pancreas procurement to reduce the warm ischemic time. To reduce the apoptosis of pancreatic tissue during cold preservation, we have applied the ductal injection of preservation solution. For pancreas preservation, we use modified Kyoto solution, which is advantageous at trypsin inhibition and less collagenase inhibition. In this paper, we show pancreas procurement and preservation in our group for islet transplantation.

scholarly journals Role of Exosomes in Islet Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Jordan Mattke ◽  
Srividya Vasu ◽  
Carly M. Darden ◽  
Kenjiro Kumano ◽  
Michael C. Lawrence ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
Graft Function ◽  
Pancreatic Islet Transplantation ◽  
Complex Molecules ◽  
Wide Range ◽  
And Function ◽  
Antigen Presenting

Exosomes are known for their ability to transport nucleic acid, lipid, and protein molecules, which allows for communication between cells and tissues. The cargo of the exosomes can have a variety of effects on a wide range of targets to mediate biological function. Pancreatic islet transplantation is a minimally invasive cell replacement therapy to prevent or reverse diabetes mellitus and is currently performed in patients with uncontrolled type 1 diabetes or chronic pancreatitis. Exosomes have become a focus in the field of islet transplantation for the study of diagnostic markers of islet cell viability and function. A growing list of miRNAs identified from exosomes collected during the process of isolating islets can be used as diagnostic biomarkers of islet stress and damage, leading to a better understanding of critical steps of the isolation procedure that can be improved to increase islet yield and quality. Exosomes have also been implicated as a possible contributor to islet graft rejection following transplantation, as they carry donor major histocompatibility complex molecules, which are then processed by recipient antigen-presenting cells and sensed by the recipient immune cells. Exosomes may find their way into the therapeutic realm of islet transplantation, as exosomes isolated from mesenchymal stem cells have shown promising results in early studies that have seen increased viability and functionality of isolated and grafted islets in vitro as well as in vivo. With the study of exosomes still in its infancy, continued research on the role of exosomes in islet transplantation will be paramount to understanding beta cell regeneration and improving long-term graft function.

scholarly journals Strain-Programmable Patch for Diabetic Wound Healing

2021 ◽  
Author(s):  
Georgios Theocharidis ◽  
Hyunwoo Yuk ◽  
Heejung Roh ◽  
Liu Wang ◽  
Ikram Mezghani ◽  
...  
Keyword(s):  
Wound Healing ◽  
Chronic Wounds ◽  
Ex Vivo ◽  
Numerical Models ◽  
Diabetic Patients ◽  
Diabetic Wound ◽  
Memory Mechanism ◽  
Culture Models ◽  
Diabetic Wound Healing

Chronic wounds with impaired healing capability such as diabetic foot ulcers (DFU) are devastating complications in diabetic patients, inflicting rapidly growing clinical and economic burdens in aging societies. Despite recent advances in therapeutic approaches, limited benefits of the existing solutions highlight the critical need for novel therapeutic solutions for diabetic wound healing. Here we propose a strain-programmable patch capable of rapid robust adhesion on and programmable mechanical contraction of wet wounded tissues over days to offer a new therapeutic platform for diabetic wounds. The strain-programmable patch, consisting of a dried bioadhesive layer and a pre-stretched elastomer backing, implements a hydration-based shape-memory mechanism to achieve both uniaxial and biaxial contractions and stress remodeling of wet wounds in a programmable manner. We develop theoretical and numerical models to rationally guide the strain-programming and mechanical modulation of wounds. In vivo rodent and ex vivo human skin culture models validate the programmability and efficacy of the proposed platform and identify mechanisms of action for accelerated diabetic wound healing.

scholarly journals In vivo vascularization and islet function in a microwell device for pancreatic islet transplantation

2021 ◽  
Author(s):  
Alexandra M. Smink ◽  
Katarzyna Skrzypek ◽  
Jolanda Visser ◽  
Rei Kuwabara ◽  
Bart J. de Haan ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
Pancreatic Islet ◽  
Islet Function ◽  
Pancreatic Islet Transplantation

Progress in Translational Regulatory T Cell Therapies for Type 1 Diabetes and Islet Transplantation

2020 ◽  
Author(s):  
Braulio A Marfil-Garza ◽  
Joshua Hefler ◽  
Mario Bermudez De Leon ◽  
Rena Pawlick ◽  
Nidheesh Dadheech ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Islet Transplantation ◽  
Ex Vivo ◽  
Severe Hypoglycemia ◽  
Cell Therapies ◽  
Current State ◽  
Cellular Transplantation ◽  
And Function

Abstract Regulatory T cells (Tregs) have become highly relevant in the pathophysiology and treatment of autoimmune diseases, such as type 1 diabetes (T1D). As these cells are known to be defective in T1D, recent efforts have explored ex vivo and in vivo Treg expansion and enhancement as a means for restoring self-tolerance in this disease. Given their capacity to also modulate alloimmune responses, studies using Treg-based therapies have recently been undertaken in transplantation. Islet transplantation provides a unique opportunity to study the critical immunological crossroads between auto- and alloimmunity. This procedure has advanced greatly in recent years, and reports of complete abrogation of severe hypoglycemia and long-term insulin independence have become increasingly reported. It is clear that cellular transplantation has the potential to be a true cure in T1D, provided the remaining barriers of cell supply and abrogated need for immune suppression can be overcome. However, the role that Tregs play in islet transplantation remains to be defined. Herein, we synthesize the progress and current state of Treg-based therapies in T1D and islet transplantation. We provide an extensive, but concise, background to understand the physiology and function of these cells and discuss the clinical evidence supporting potency and potential Treg-based therapies in the context of T1D and islet transplantation. Finally, we discuss some areas of opportunity and potential research avenues to guide effective future clinical application. This review provides a basic framework of knowledge for clinicians and researchers involved in the care of patients with T1D and islet transplantation.

scholarly journals Biocompatibility of a Marine Collagen-Based Scaffold In Vitro and In Vivo

Marine Drugs ◽  
2020 ◽  
Vol 18 (8) ◽  
pp. 420
Author(s):  
Dafna Benayahu ◽  
Leslie Pomeraniec ◽  
Shai Shemesh ◽  
Snir Heller ◽  
Yoav Rosenthal ◽  
...  
Keyword(s):  
Plasma Cells ◽  
3D Structure ◽  
Tendon Repair ◽  
Inflammatory Cells ◽  
Well Being ◽  
Biological Properties ◽  
Target Tissue ◽  
Post Transplantation

Scaffold material is essential in providing mechanical support to tissue, allowing stem cells to improve their function in the healing and repair of trauma sites and tissue regeneration. The scaffold aids cell organization in the damaged tissue. It serves and allows bio mimicking the mechanical and biological properties of the target tissue and facilitates cell proliferation and differentiation at the regeneration site. In this study, the developed and assayed bio-composite made of unique collagen fibers and alginate hydrogel supports the function of cells around the implanted material. We used an in vivo rat model to study the scaffold effects when transplanted subcutaneously and as an augment for tendon repair. Animals’ well-being was measured by their weight and daily activity post scaffold transplantation during their recovery. At the end of the experiment, the bio-composite was histologically examined, and the surrounding tissues around the implant were evaluated for inflammation reaction and scarring tissue. In the histology, the formation of granulation tissue and fibroblasts that were part of the inclusion process of the implanted material were noted. At the transplanted sites, inflammatory cells, such as plasma cells, macrophages, and giant cells, were also observed as expected at this time point post transplantation. This study demonstrated not only the collagen-alginate device biocompatibility, with no cytotoxic effects on the analyzed rats, but also that the 3D structure enables cell migration and new blood vessel formation needed for tissue repair. Overall, the results of the current study proved for the first time that the implantable scaffold for long-term confirms the well-being of these rats and is correspondence to biocompatibility ISO standards and can be further developed for medical devices application.

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