Uncovering shared Molecular and Histopathological features of accepted versus rejected donor livers for transplantation
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ABSTRACT:
PROVIDER: PRJNA1020411 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26156500_1.fastq.gz | Fastqsanger.gz | |||
| SRR26156500_2.fastq.gz | Fastqsanger.gz | |||
| SRR26156501_1.fastq.gz | Fastqsanger.gz | |||
| SRR26156501_2.fastq.gz | Fastqsanger.gz | |||
| SRR26156502_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
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Project description:Liver transplantation is the only treatment option for patients with end-stage liver disease. However, a persistent disparity remains between supply and demand for donor organs suitable for transplantation, resulting in a waiting list mortality of up to 20%. This has resulted in an increasing use of high-risk grafts from suboptimal, extended criteria donors, including livers from donation after circulatory death (DCD) donors, and donors with significant comorbidities such as advanced age, diabetes mellitus and livers with high fat content. While cold storage remains sufficient for livers considered optimal for transplantation, ECD grafts are more vulnerable to cold ischemic damage, resulting in many of these grafts being rejected. As an alternative to cold storage, ex-situ normothermic machine perfusion (NMP) has become an increasingly popular method for preservation, transportation and assessment of ECD livers prior to transplantation. This allows for functional assessment of the graft and provides the opportunity to assess key processes that can be used to determine organ viability. The use of both hepatocellular and biliary viability criteria in selection of suboptimal livers from ECD donors has led to the successful transplantation of these grafts with a low incidence of post-transplant cholangiopathies. However, the mechanisms of biliary injury, and recovery thereof, following static cold storage remains poorly understood. Insight into these mechanisms may further improve preservation and selection of ECD livers. Therefore, we performed an in-depth proteomics analysis of bile samples collected from human ECD livers during NMP to identify potential mechanisms linked to biliary injury, function and regeneration over the course of the perfusion, and to assess whether biliary protein profiles can distinguish between transplantable and non-transplantable grafts.
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Project description:Normothermic machine perfusion (NMP) after static cold storage is increasingly used for preservation and assessment of human donor livers prior to transplantation. Biliary viability assessment during NMP reduces the risk of post-transplant biliary complications. However, understanding molecular changes in the biliary system during NMP remains incomplete. Here, we performed RNA-seq analysis of donor livers undergoing NMP treatment and compared livers with biliary viability scores that were acceptable for transplantation vs those that were not.
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Project description:BackgroundDonor liver biopsy (DLBx) in liver transplantation provides information on allograft quality; however, predicting outcomes from these allografts remains difficult.MethodsBetween 2006 and 2015, 16 691 transplants with DLBx were identified from the Standard Transplant Analysis and Research database. Cox proportional hazard regression analyses identified donor and recipient characteristics associated with 30-d, 90-d, 1-y, and 3-y graft survival. A composite model, the Liver Transplant After Biopsy (LTAB) score, was created. The Mini-LTAB was then derived consisting of only donor age, macrosteatosis on DLBx, recipient model for end-stage liver disease score, and cold ischemic time. Risk groups were identified for each score and graft survival was evaluated. P values <0.05 were considered significant.ResultsThe LTAB model used 14 variables and 5 risk groups and identified low-, mild-, moderate-, high-, and severe-risk groups. Compared with moderate-risk recipients, severe-risk recipients had increased risk of graft loss at 30 d (hazard ratio, 3.270; 95% confidence interval, 2.568-4.120) and at 1 y (2.258; 1.928-2.544). The Mini-LTAB model identified low-, moderate-, and high-risk groups. Graft survival in Mini-LTAB high-risk transplants was significantly lower than moderate- or low-risk transplants at all time points.ConclusionsThe LTAB and Mini-LTAB scores represent guiding principles and provide clinically useful tools for the successful selection and utilization of marginal allografts in liver transplantation.
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Project description:BackgroundIschemia-free liver transplantation (IFLT) has been innovated to avoid graft ischemia during organ procurement, preservation, and implantation. However, the metabolism activity of the donor livers between in the in situ and ex situ normothermic machine perfusion (NMP) conditions, and between standard criteria donor and extend criteria donor remains unknown.MethodsDuring IFLT, plasma samples were collected both at the portal vein and hepatic vein of the donor livers in situ during procurement and ex situ during NMP. An ultra-high performance liquid chromatography-mass spectrometry was conducted to investigate the common and distinct intraliver metabolite exchange.ResultsProfound cysteine and methionine metabolism, and aminoacyl-tRNA biosynthesis were found in both in situ and ex situ conditions. However, obvious D-arginine and D-ornithine metabolism, arginine and proline metabolism were only found in the in situ condition. The suppressed activities of the urea cycle pathway during ex situ condition were confirmed in an RNA expression level. In addition, compared with extend criteria donor group, standard criteria donor group had more active intraliver metabolite exchange in metabonomics level. Furthermore, we found that the relative concentration of p-cresol, allocystathionine, L-prolyl-L-proline in the ex situ group was strongly correlated with peak alanine aminotransferase and aspartate aminotransferase at postoperative days 1-7.ConclusionsIn the current study, we show the common and distinct metabolism activities during IFLT. These findings might provide insights on how to modify the design of NMP device, improve the perfusate components, and redefine the criteria of graft viability.
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