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Uncovering shared Molecular and Histopathological features of accepted versus rejected donor livers for transplantation

ABSTRACT: Liver transplantation is the solution for acute or chronic liver failure. There is an unmet demand for liver transplantation, as not all donated organs are transplanted. The clinical selection criteria for donated livers depends on histopathological evaluation and liver function tests. A fraction of the donor livers are rejected for transplantation due to the variability in applying the selection criteria. We applied an integrated transcriptomics and histopathological approach to characterize the donor livers evaluated for transplantation. We obtained liver biopsies from deceased donors during organ collection (n=10 accepted and n= 21 rejected for transplantation). We performed RNA sequencing to characterize the global gene expression profiles. We assessed steatosis, fibrosis, and necrosis via manual histopathological evaluation and a custom artificial intelligence-based image analysis. We identified two transcriptomically distinct subsets in the rejected donor liver group (termed rejected-1 and rejected-2), where the rejected-2 subset had a near complete transcriptomic overlap with the accepted livers, suggesting the potential for acceptability from a molecular standpoint. The liver metabolic functional genes were similarly upregulated in the accepted and rejected-2 groups compared to the rejected-1 subset. Expression levels of several extracellular matrix genes were similarly low in the accepted and rejected-2 groups compared to the rejected-1 subset. Filtering the rejected-2 subset based on histopathological evaluation identified the cases with borderline scores and extensive molecular overlap with the accepted group. Our integrated molecular and histopathological approach identified a subset of rejected donor livers that may be suitable for transplantation, thereby expanding the pool of transplantable livers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243887 | GEO | 2024/04/18

REPOSITORIES: GEO

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Project description:INTRODUCTION Ischemia and reperfusion injury (IRI)-elicited tissue injury contributes to morbidity and mortality in a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest 1. Ischemia-reperfusion injury is also a major challenge during organ transplantation and cardiothoracic, vascular and general surgery 1. IRI, one of the biggest challenges for organ transplantation, continues to be a vital source of morbidity among recipients, especially in liver transplantation 2. With the enlarging shortage of available donor livers, the increased use of extended criteria donor grafts further increases IRI, adversely affecting both short-term and long-term outcomes of graft and patient survival 3. Numerous studies have investigated the benefits of pharmacological, heat shock, and ischemic preconditioning interventions aimed at decreasing liver IRI 4. However, the benefit was limited. Our center has been making great effort in conquering IRI and have developed a novel surgical technique called ischemia-free liver transplantation 5. It is an ultimate method to overcome IRI in liver transplantation, but there is still a long way to popularize it. As a result, it is still of great significance to study IRI and identify the core genes in the process and the underlying mechanism. Comprehensive bioinformatics analysis has been increasingly important as a method to study various pathological and physiological condition 6. By enrolling multiple omics or combining different types of omics, comprehensive bioinformatics analysis was able to recognize key factors that could have potentially pathogenic impact such as gene expression, protein function, and downstream pathways. With the rapid development of high-throughput sequencing technologies, several transcriptomic datasets on IRI of liver transplantation have become available in the Gene Expression Omnibus (GEO) database. Herein, we recruited 3 GEO datasets to conduct comprehensive analysis with the GEO dataset from our center. Moreover, we performed the first proteome of liver tissues to study liver IRI. Then the transcriptome and proteome were used for combined analysis to reveal key factors in liver IRI.

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Uncovering shared Molecular and Histopathological features of accepted versus rejected donor livers for transplantation

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