Acute Ischemia Induced by High Density Culture Increases Cytokine Expression and Diminishes the Function and Viability of Highly Purified Human Islets of Langerhans.

Background: Encapsulation devices have the potential to enable cell based insulin replacement therapies (such as human islet or stem cell derived [beta] cell transplantation) without immunosuppression. However, reasonably sized encapsulation devices promote ischemia due to high [beta] cell densities creating prohibitively large diffusional distances for nutrients. It is hypothesized that even acute ischemic exposure will compromise the therapeutic potential of cell based insulin replacement. In this study, the acute effects of high-density ischemia were investigated in human islets to develop a detailed profile of early ischemia induced changes and targets for intervention. Methods: Human islets were exposed in a pairwise model simulating high density encapsulation to normoxic or ischemic culture for 12 hours, after which viability and function were measured. RNA sequencing (RNAseq) was conducted to assess transcriptome-wide changes in gene expression. Results: Islet viability after acute ischemic exposure was reduced compared to normoxic culture conditions (p

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