Rat islet cell aggregates are superior to islets for transplantation in microcapsules

Abstract

Aims/hypothesis Islet transplantation is a promising treatment for type 1 diabetes but is hampered by a shortage of donor human tissue and early failure. Research on islet-cell transplantation includes finding new sources of cells and immunoisolation to protect from immune assault and tumorigenic potential. Small islet-cell aggregates were studied to determine if their survival and function were superior to intact islets within microcapsules because of reduced oxygen transport limitation and inflammatory mediators. Methods Islet-cell aggregates were generated by dispersing rat islets into single cells and allowing them to re-aggregate in culture. Rat islets and islet-cell aggregates were encapsulated in barium alginate capsules and studied when cultured in low (0.5% or 2%) or normal (20%) oxygen, or transplanted into mice. Results Encapsulated islet-cell aggregates were able to survive and function better than intact islets in terms of oxygen-consumption rate, nuclei counts, insulin-to-DNA ratio, and glucose-stimulated insulin secretion. They also had reduced expression of pro-inflammatory genes. Islet-cell aggregates showed reduced tissue necrosis in an immunodeficient transplant model and a much greater proportion of diabetic xenogeneic transplant recipients receiving islet-cell aggregates (tissue volume of only 85 islet equivalents) had reversal of hyperglycaemia than recipients receiving intact islets. Conclusions/interpretation These aggregates were superior to intact islets in terms of survival and function in low-oxygen culture and during transplantation and are likely to provide more efficient utilisation of islet tissue, a finding of importance for the future of cell therapy for diabetes.

Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice

“…A recent study using encapsulated islets, which are unable to revascularise, demonstrated improved transplantation outcomes from grafting of aggregates of smaller islets rather than of larger intact islets, consistent with an anatomical effect on function that is independent of revascularisation or endothelial cell density [43]. It is well established that islet organisation influences function by facilitating the numerous interactions between the islet cells [44] that are required for normal insulin secretion [45,46].…”

Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist

“…E-mail: andrew.schally@va.gov. small islet cell clusters to reduce the diffusion distance to the islet (30)(31)(32), and the use of islets engineered to contain an intracellular oxygen carrier such as myoglobin (33). Another approach focuses on in situ generation of oxygen, close to the islets, by an electrochemical process (34) or local photosynthesis (35).…”

Avoiding Immunosuppression for Islet Transplantation: Use of Protective Biomaterials

“…Comparatively, alginate has excellent biocompatibility, hydrophilic properties, easy gelation process, stable architecture, and relatively low cost. Alginate is polysaccharide derived from seaweed, which can be highly purified to prevent foreign body response [38]. Impure alginate has been implicated in islet cell necrosis and recruitment of inflammatory mediators [39].…”

“…This polysaccharide can contain varying concentrations of M and G carbohydrates, which provides a variety of molecular weight, stability, permeability, and immunogenicity. High G alginates form gels, which are smaller and stronger than high M alginates [38]. High-M alginate was often avoided when immunosuppression was the desired outcome, because mannuronic acid tends to provoke both innate and antibody-mediated immune response, independent of the type of cation used for cross-linking (Ca 2+ or Ba…”

“…Cross-linking establish a mesh of porous material that allows bidirectional flow of materials, including oxygen, nutrients, and hormones (especially insulin). However, hydrogel polymerization does not result in uniform pore size, while internal permeability tends to vary between batches [38].…”