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Differences in gene expression in islets isolated from pancreata donated after Cardiac Death relative to Brain Death

ABSTRACT: The decreasing numbers of Donation after Brain Death (DBD) donors necessitates the comprehensive evaluation of Donation after Cardiac Death Donors (DCD) as a source of pancreata. The aim of this study was to characterize pancreata and islets from DCD and DBD donors with respect to markers of cellular stress that may indicate compromised islet quality. Immunohistochemical staining of pre-isolation pancreas biopsies found increased numbers of caspase 3 positive islets in DBD, while markers of oxidative stress (nitrotyrosine, CML, and HNE) were elevated in DCD. Assessment of islet quality by standard (yield, morphology, fluorescence microscopy, and glucose stimulated insulin secretion) and novel methods (flow cytometry, HPLC quantification of ATP) did not reveal significant differences. However, the post culture loss of DCD islets was increased compared to DBD, and DCD islets showed delayed functional potency when transplanted into diabetic NOD.scid mice. Microarray analysis of cultured islets showed increased expression of multiple stress pathway related genes in DCD compared to DBD. Together these data indicate that the current standard donor management, pancreas recovery and preservation practices are insufficient to quench the oxidative stress injury suffered by DCD islets which leads to loss in culture and may complicate their use in clinical transplant. Keywords: cell type comparison

ORGANISM(S): Homo sapiens

PROVIDER: GSE14839 | GEO | 2010/02/09

SECONDARY ACCESSION(S): PRJNA112107

REPOSITORIES: GEO

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Project description:Ischemia-reperfusion injury during liver transplantation is responsible for early allograft dysfunction (EAD) and failure, both of which are associated with a high risk of morbidity and mortality in the recipient. The purpose of this study was to study major transcriptional alterations in livers procured from different types of human liver donors in order to identify genetic profiles predictive of post-implantation function. We have analyzed samples form living donors (LD), donors after cardiac death (DCD), donors after brain death, with subsequent post-implantation EAD in the recipient (DBD-EAD); and donors after brain death without EAD (DBD). Two samples were obtained from each donor: sample A was taken immediately before cold perfusion (baseline) and sample B 2h after portal reperfusion. We identified clear differences in gene expression patterns according to donor source. Both samples A and B from DBD-EAD and DCD demonstrated over-expression of pro-apoptotic and inflammatory transcripts. However, in DBD and LD, expression of these genes was low at baseline and rose only after reperfusion. DBD and LD demonstrated the greatest increase in overall genetic expression after reperfusion when sample B was contrasted with A, indicating less baseline graft injury in these two groups. Grafts from LD were characterized by activation of transcripts related to anti-ischemic and regenerative processes and fewer pro-inflammatory gene transcripts. This transcriptional events occurring in liver allografts could allow for the prediction of post-transplant function. Pro-inflammatory and ischemic transcriptional changes in the grafts are directly related to donor type and may be useful targets for the development of future therapeutic strategies. The complete database comprised the expression for samples taken from 33 liver grafts. Sample A was taken immediately before cold perfusion (baseline) and sample B 2 h after portal reperfusion. Donors were from one of four groups: living (LD); after cardiac death (DCD); after brain death, with subsequent post-implantation EAD in the recipient (DBD-EAD); and after brain death without EAD (DBD). RNA was extracted from the 66 samples and analyzed using Illumina Beadarray technology. A group of 3 samples from healthy volunteers and 3 samples form LD taken at the start of surgery are included as controls or reference samples. This dataset is part of the TransQST collection.

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Differences in gene expression in islets isolated from pancreata donated after Cardiac Death relative to Brain Death

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