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Home | Seminars and Symposia | Past seminars/symposia: Monday, November 7, 2005

Transcriptional crosstalk in isolated porcine islets responding to hyperglycemia and cytokine stress

by

Scott Fahrenkrug
Genetics Department of Animal Science

Monday, November 7, 2005
2:30 pm

402 Walter Library

Download slides (pdf 1.2 MB) Xenotransplantation of adult porcine islets could meet an increasing demand for cell-based diabetes therapy. An effort to deploy islet xenotranplantation on a large scale would need to institute rigorous safety and quality control measures to maximize transplant success. Development of molecular tools to monitor porcine islet cellular responses to ischemic, osmotic, mechanical and oxidative stresses during islet cell processing and post-isolation culturing would aid the rational design of cytoprotective strategies aimed at improving transplant outcomes. In addition, gene expression signatures informative for islet quality could serve as an adjunct to physiological testing to establish the suitability of islet products for transplantation. In order to identify molecular hallmarks of porcine islet function and viability we have monitored the transcriptional profile of cultured adult pig islets using a porcine 70-mer oligonucleotide microarray and real-time PCR. Profiles of normal islet cells were compared to islet cells cultured under stress conditions for 48 hours with elevated glucose (16.7 mM), inflammatory cytokines (IL-1beta: 2 ng/ml; TNF-alpha: 1,000 U/ml; and IFN-gamma: 1,000 U/ml), or both. Islet cells cultured under conditions of elevated glucose expressed genes previously proposed as indicators of insulin demand and glucose-induced stress response long before islet dysfunction indicators are observed by traditional physiological measurements. Cytokine treatment resulted in increased expression of genes indicative of cytokine-induced stress response and beta cell dysfunction. Notably, the transcriptional response of porcine islets to glucose and cytokines were partly overlapping, revealing regulatory checkpoints common to these two distinct types of stress. Markers common to hyperglycemia and islet inflammation may serve as novel targets for improving and reporting on isolated porcine islet function and viability.