Proteomics in Liver Transplantation: A Systematic Review

Abstract

BackgroundAlthough proteomics has been employed in the study of several models of liver injury, proteomic methods have only recently been applied not only to biomarker discovery and validation but also to improve understanding of the molecular mechanisms involved in transplantation.MethodsThe study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology and the guidelines for performing systematic literature reviews in bioinformatics (BiSLR). The PubMed, ScienceDirect, and Scopus databases were searched for publications through April 2020. Proteomics studies designed to understand liver transplant outcomes, including ischemia-reperfusion injury (IRI), rejection, or operational tolerance in human or rat samples that applied methodologies for differential expression analysis were considered.ResultsThe analysis included 22 studies after application of the inclusion and exclusion criteria. Among the 497 proteins annotated, 68 were shared between species and 10 were shared between sample sources. Among the types of studies analyzed, IRI and rejection shared a higher number of proteins. The most enriched pathway for liver biopsy samples, IRI, and rejection was metabolism, compared to cytokine-cytokine receptor interactions for tolerance.ConclusionsProteomics is a promising technique to detect large numbers of proteins. However, our study shows that several technical issues such as the identification of proteoforms or the dynamic range of protein concentration in clinical samples hinder the successful identification of biomarkers in liver transplantation. In addition, there is a need to minimize the experimental variability between studies, increase the sample size and remove high-abundance plasma proteins.

Proteomics: Its Promise and Pitfalls in Shaping Precision Medicine in Solid Organ Transplantation

“…Conventional proteomic screens currently miss protein functional changes 160 such as PTMs, interactions with other molecules, cleavages, and isoforms. Therefore, the future of proteomics could lie in the improvement of the identification of protein isoforms, PTMs, or gene variants giving rise to altered structure/function (proteoforms) 61,68 that are implicated in the regulation of several biological mechanisms underlying pathophysiological processes. Recently, several studies presented state-of-the-art technologies and workflows for large-mapping of protein structures for mechanistic understanding of proteome function and regulation in health and disease.…”

“…Additionally, integration of proteomics data with those from other techniques, such as genomics, transcriptomics, and metabolomics, is expected to provide more comprehensive snapshots and a deeper understanding of the mechanisms involved in the pathophysiology after solid organ transplantation. 68 Novel computational methods, including artificial intelligence, are enabling integration methods that reveal what is fundamental in a data set and even provide causal inferences. Although such approaches hold the key to precision medicine, large and carefully annotated data sets will prove necessary.…”

“…[62][63][64] Twodimensional gel 65,66 and capillary electrophoresis (CE) 67 were initially used for separation of peptides/proteins before mass spectrometric analysis but have been mostly replaced by shotgun proteomics. 68 In this approach, separation of peptides is achieved through LC and is followed by their ionization. 62,63 The most common ionization techniques that are currently used include electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI).…”

Liver Graft Proteomics Reveals Potential Incipient Mechanisms behind Early Renal Dysfunction after Liver Transplantation

“…This dataset differs significantly from the limited available proteomics data in human livers undergoing ischemia–reperfusion injury or transplantation [ 27 ]. An explanation is the different study design and hypothesis but also the state-of-the-art proteomics used herein.…”

“…This analysis adds novel and comprehensive information on the proteome of liver grafts in patients ultimately developing AKI. This hypothesis has not been addressed so far as most studies focused on the development and analysis of HIRI [ 27 ]. A strength of this study is the high-performing global mass spectrometry used herein, allowing us to identify over four thousand distinct proteins and allowing its quantitative assessment.…”