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Published on: December 21, 2016
Examination of the molecular signature associated with islet dysfunction
1University of Tennessee, Memphis, Tennessee 38103, USA.
Abstract:
The aim of this study was to identify the molecular signatures that are predictive of nonfunctional islet preparations. We examined functional outcomes of six islet preparations accepted for research purposes from human donors. Islet were maintained on culture in M-SFM media for 7 to 14 days then transplanted into NOD-SCID mice. At the time of transplant, RNA was extracted from a second aliquot of cultured islets for expression analysis. We also performed gene expression analysis using high-density Affymetrix U133A GeneChips on these preparations. Among 1833 genes selected, hierarchical clustering was performed using the GeneSpring software package (Silicon Genetics, Inc.), where 754 genes (higher in nonfunctional) and 177 genes (lower in nonfunctional) were differentially expressed with tight pattern of expression. Islets with low functionality showed high relative levels of expression of hypoxia-induced genes and increased frequency of expression of proinflammatory and proangiogenic genes, such as vascular endothelial growth factor. Conversely, nonfunctional islets had low levels of insulin-processing message. The general profile of these low-functionality islets shows attempted recovery from hypoxic assault and little effort directed toward insulin production and secretion. Further identification of the molecular signature of nonfunctional islets could allow the development of a potency assay for human transplantation.
Insights
Researchers identified molecular signatures in nonfunctional islet preparations. Low-functionality islets show hypoxia-induced genes and reduced insulin production, aiding in developing a potency assay for islet transplantation.
Area of Science:
- * Molecular biology
- * Immunology
- * Regenerative medicine
Background:
- * Islet transplantation is a promising therapy for type 1 diabetes.
- * Assessing the viability and function of islet preparations is critical for successful transplantation.
- * Current methods for evaluating islet quality are limited.
Purpose of the Study:
- * To identify molecular signatures that predict nonfunctional human islet preparations.
- * To understand the biological processes underlying islet dysfunction.
- * To lay the groundwork for a potency assay for islet transplantation.
Main Methods:
- * Six human islet preparations were cultured and transplanted into NOD-SCID mice.
- * Gene expression analysis was performed on cultured islets using high-density microarrays.
- * Hierarchical clustering identified differentially expressed genes associated with islet function.
Main Results:
- * 754 genes were upregulated and 177 genes were downregulated in nonfunctional islets.
- * Nonfunctional islets exhibited increased expression of hypoxia-induced, proinflammatory, and proangiogenic genes (e.g., vascular endothelial growth factor).
- * Nonfunctional islets showed reduced expression of insulin-processing genes.
Conclusions:
- * Molecular signatures can predict the functionality of islet preparations.
- * Nonfunctional islets display a profile of attempted recovery from hypoxia with impaired insulin production.
- * Identifying these signatures could lead to a potency assay for human islet transplantation.
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