Oxygen environment and islet size are the primary limiting factors of isolated pancreatic islet survival

Abstract

BackgroundType 1 diabetes is an autoimmune disease that destroys insulin-producing beta cells in the pancreas. Pancreatic islet transplantation could be an effective treatment option for type 1 diabetes once several issues are resolved, including donor shortage, prevention of islet necrosis and loss in pre- and post-transplantation, and optimization of immunosuppression. This study seeks to determine the cause of necrotic loss of isolated islets to improve transplant efficiency.MethodologyThe oxygen tension inside isolated human islets of different sizes was simulated under varying oxygen environments using a computational in silico model. In vitro human islet viability was also assessed after culturing in different oxygen conditions. Correlation between simulation data and experimentally measured islet viability was examined. Using these in vitro viability data of human islets, the effect of islet diameter and oxygen tension of the culture environment on islet viability was also analyzed using a logistic regression model.Principal findingsComputational simulation clearly revealed the oxygen gradient inside the islet structure. We found that oxygen tension in the islet core was greatly lower (hypoxic) than that on the islet surface due to the oxygen consumption by the cells. The hypoxic core was expanded in the larger islets or in lower oxygen cultures. These findings were consistent with results from in vitro islet viability assays that measured central necrosis in the islet core, indicating that hypoxia is one of the major causes of central necrosis. The logistic regression analysis revealed a negative effect of large islet and low oxygen culture on islet survival.Conclusions/SignificanceHypoxic core conditions, induced by the oxygen gradient inside islets, contribute to the development of central necrosis of human isolated islets. Supplying sufficient oxygen during culture could be an effective and reasonable method to maintain isolated islets viable.

Microencapsulated adult porcine islets transplanted intraperitoneally in streptozotocin‐diabetic non‐human primates

“…One of the most striking observations from these studies was provided by histological analysis of capsules collected from the peritoneum of the animals, either at biopsy or at necropsy. A consistent finding was that many islets were fragmented and/or had necrotic cores, strongly indicating hypoxic damage, 60 although healthy-appearing islets were also found ( Figure 5A [insets],G,H).…”

Biomaterials for Personalized Cell Therapy

“…Biomaterials can be designed to address the challenge of limited oxygen supply for encapsulated cells. This hypoxia can cause detrimental effects on cell behavior or lead to cell death . Cells in the core of encapsulation devices may be exposed to particularly low oxygen levels, resulting in reduced secretion of therapeutic proteins due to changes in metabolic behavior .…”

Tissue‐engineered islet‐like cell clusters generated from adipose tissue‐derived stem cells on three‐dimensional electrospun scaffolds can reverse diabetes in an experimental rat model and the role of porosity of scaffolds on cluster differentiation

“…Isolated islets and ILCs differentiated from stem cells lack microvasculature hence the oxygen and nutrient supply to the core of the cluster depends on diffusion (Giuliani et al, 2005). As the radius of the islet cluster (diffusion distance) increases, the oxygen tension and nutrient supply decrease toward the core of the islet cluster resulting in necrosis of the core (Komatsu et al, 2017).…”

“…Cell-scaffold has been shown to regulate survival, insulin secretion, and preservation of spherical morphology (Aloysious & Nair, 2014;Muthyala et al, 2011;Stendahl, Kaufman, & Stupp, 2009) In this study, we could show that the size of islet-like clusters after differentiation is influenced by the pore size of the scaffolds. As the radius of the islet cluster (diffusion distance) increases, the oxygen tension and nutrient supply decrease toward the core of the islet cluster resulting in necrosis of the core (Komatsu et al, 2017). The ILCs formed on conventional electrospun scaffolds varied in size, shape, and spheroid morphology and ILCs formed on tissue culture plates were large in the size range of 282.78 ± 27.18 μm which were free-floating without attachment to the matrix and tended to fuse in medium to form a large irregular mass of cells.…”