Reduction of diffusion barriers in isolated rat islets improves survival, but not insulin secretion or transplantation outcome

Williams, S. Janette; Huang, Han-Hung; Kover, Karen; Moore, Wayne V.; Berkland, Cory; Singh, Milind; Смирнова, И. С.; Macgregor, Ronal R.; Stehno‐Bittel, Lisa

doi:10.4161/org.6.2.10373

Cited by 41 publications

(53 citation statements)

References 37 publications

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“…Previously, Williams et al reported that rat islets treated with papain became frangible and did not improve the outcome of islet transplantation in a syngenic model. 36,37 Thus, their report supports our results. It is presumed that such a fragmented islet structure may accumulate damage over time and eventually affect islet viability and functions negatively in vivo, which would not support long-term engraftment.…”

Section: Discussionsupporting

confidence: 90%

Pretreatment of donor islets with papain improves allograft survival without systemic immunosuppression in mice

Kumano

Nishinakamura

Mera

et al. 2016

Islets

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Although current immunosuppression protocols improve the efficacy of clinical allogenic islet transplantation, T cell-mediated allorejection remains unresolved, and major histocompatibility complexes (MHCs) play a crucial role in this process. Papain, a cysteine protease, has the unique ability to cleave the extracellular domain of the MHC class I structure. We hypothesized that pretreatment of donor islets with papain would diminish the expression of MHC class I on islets, reducing allograft immunogenicity and contributing to prolongation of islet allograft survival. BALB/ c islets pretreated with papain were transplanted into C57BL/6J mice as an acute allorejection model. Treatment with 1 mg/mL papain significantly prolonged islet allograft survival. In vitro, to determine the inhibitory effect on T cell-mediated alloreactions, we performed lymphocyte proliferation assays and mixed lymphocyte reactions. Host T cell activation against allogenic islet cells was remarkably suppressed by pretreatment of donor islet cells with 10 mg/mL papain. Flow cytometric analysis was also performed to investigate the effect of papain treatment on the expression of MHC class I on islets. One or 10 mg/mL papain treatment reduced MHC class I expression on the islet cell surface. Pretreatment of donor islets with papain suppresses MHC class Imediated allograft rejection in mice and contributes to prolongation of islet allograft survival without administration of systemic immunosuppressants. These results suggest that pretreatment of human donor islets with papain may reduce the immunogenicity of the donor islets and minimize the dosage of systemic immunosuppressants required in a clinical setting.

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Section: Discussionsupporting

confidence: 90%

Pretreatment of donor islets with papain improves allograft survival without systemic immunosuppression in mice

Kumano

Nishinakamura

Mera

et al. 2016

Islets

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“…However, islets are highly vascularized microtissues, and once they are isolated from the pancreas they can only rely on diffusion for nutrients in cultures. For this reason, the incubation time is very important and needs to be optimized to maintain islet viability . After we prepared the ALG islets, they were incubated at 37 °C in a humidified atmosphere of 5% CO 2 .…”

Section: Resultsmentioning

confidence: 99%

The preservation of islet with alginate encapsulation in the process of transportation

Zhang

Xiu

et al. 2015

Biotech and App Biochem

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Restoration of insulin secretion by transplantation of isolated islets is a treatment for type Ι diabetes mellitus. One of the major issues with clinical treatment of islet transplantation is how to maintain islet viability during transportation from the donor to the patient. We developed a method that uses alginate encapsulation to protect islets from mechanical damage during shipment. We tested several variables for their impact on islet viability during transportation and used the significant variable to build a response surface methodology (RSM) model by the Box-Behnken design method. This type of model is a mathematical and statistical technique that we used to optimize the conditions for islet viability during shipment. In this study, the factors that significantly affected islet survival rate were incubation time, serum concentration, and preservation time. Then, an empirical model was built to optimize conditions of the islets for shipping according to the responses of the effect factors with RSM. This model can be used to predict the islet survival rate and can serve as a guide for optimizing the transportation method of islets and increasing the success rate of the transplant procedure.

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“…Molecules that are critical for islet survival and function, including oxygen, nutrients, and insulin, are exchanged through diffusion across the polymeric capsule (13). Such passive transport is limited to a distance of ∼150 μm, which is significantly (∼10-50%) smaller than the half-length/radial distance of most devices (14,15). Diffusion limitations may result in blunted secretion of trophic factors in response to host stimulation (e.g., insulin in response to elevations in glucose) and in core necrosis.…”

mentioning

confidence: 99%

Device design and materials optimization of conformal coating for islets of Langerhans

Tomei

Manzoli

Fraker

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

174

145

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Encapsulation of islets of Langerhans may represent a way to transplant islets in the absence of immunosuppression. Traditional methods for encapsulation lead to diffusional limitations imposed by the size of the capsules (600-1,000 μm in diameter), which results in core hypoxia and delayed insulin secretion in response to glucose. Moreover, the large volume of encapsulated cells does not allow implantation in sites that might be more favorable to islet cell engraftment. To address these issues, we have developed an encapsulation method that allows conformal coating of islets through microfluidics and minimizes capsule size and graft volume. In this method, capsule thickness, rather than capsule diameter, is constant and tightly defined by the microdevice geometry and the rheological properties of the immiscible fluids used for encapsulation within the microfluidic system. We have optimized the method both computationally and experimentally, and found that conformal coating allows for complete encapsulation of islets with a thin (a few tens of micrometers) continuous layer of hydrogel. Both in vitro and in vivo in syngeneic murine models of islet transplantation, the function of conformally coated islets was not compromised by encapsulation and was comparable to that of unencapsulated islets. We have further demonstrated that the structural support conferred by the coating materials protected islets from the loss of function experienced by uncoated islets during ex vivo culture.cell encapsulation | polyethylene glycol | alginate | cell transplantation

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Reduction of diffusion barriers in isolated rat islets improves survival, but not insulin secretion or transplantation outcome

Cited by 41 publications

References 37 publications

Pretreatment of donor islets with papain improves allograft survival without systemic immunosuppression in mice

Pretreatment of donor islets with papain improves allograft survival without systemic immunosuppression in mice

The preservation of islet with alginate encapsulation in the process of transportation

Device design and materials optimization of conformal coating for islets of Langerhans

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