Impact of liver failure on the circulating extracellular vesicle miRNA repertoire

Sotiris Mastoridis; Vishal Patel; Sofia Christakoudi; Juan Jose Lozano; Siamak Salehi; Ada Kurt; Cathleen Grossart; Elisavet Kodela; Marc Martinez-Llordella; Alberto Sanchez-Fueyo

doi:10.1111/hepr.13909

Impact of liver failure on the circulating extracellular vesicle miRNA repertoire

Hepatol Res. 2023 Aug;53(8):771-785. doi: 10.1111/hepr.13909. Epub 2023 May 2.

Authors

Sotiris Mastoridis^{1

2}, Vishal Patel^{1

3

4}, Sofia Christakoudi^{5

6}, Juan Jose Lozano⁷, Siamak Salehi¹, Ada Kurt¹, Cathleen Grossart¹, Elisavet Kodela^{1

3}, Marc Martinez-Llordella¹, Alberto Sanchez-Fueyo^{1

3}

Affiliations

¹ Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
² Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
³ Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.
⁴ The Roger Williams Institute of Hepatology (Foundation for Liver Research), London, UK.
⁵ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
⁶ Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
⁷ Bioinformatic Platform, Biomedical Research Centre in Hepatic and Digestive Diseases, Instituto de Salud Carlos III, Madrid, Spain.

PMID: 37060575
DOI: 10.1111/hepr.13909

Abstract

Background & aims: Cell-derived small extracellular vesicles (sEVs) participate in cell-cell communication via the transfer of molecular cargo including selectively enriched microRNAs (miRNAs). Utilizing advances in sEV isolation and characterization, this study investigates the impact of liver injury and dysfunction on the circulating EV-miRNA profile.

Methods: High-throughput screening of 799 sEV-miRNAs isolated from plasma was performed in patients across a spectrum of liver disorders including compensated and decompensated chronic liver disease, acute-on-chronic liver failure (ACLF), and acute liver failure, in addition to healthy controls and those with severe sepsis. miRNA levels were compared with clinical and biochemical parameters, composite scores of liver disease, and patient outcomes.

Results: miRNA screening revealed the degree of hepatic dysfunction to be the main determinant of changes in circulating sEV-miRNA profile, with liver-specific miRNA-122 being among the most highly dysregulated in severe injury. Principal components analyses of the 215 differentially expressed miRNAs showed differing profiles, particularly among those with acute liver injury and ACLF. A distinct profile of dysregulated miRNA, but not circulating cytokines, was shown to characterize ACLF, with four consensus miRNAs identified-miR-320e, miR-374-5p, miR-202-3p, and miR-1910-5p. High miR-320e was associated with poorer 90-day survival (p = 0.014) and regulated the functional gene targets IK, RPS5, MANBAL, and PEBP1.

Conclusions: This first comprehensive analysis to the best of our knowledge of patients with varying degrees and stages of liver failure demonstrates miRNA profiles specifically within the sEV compartment to be significantly altered in progressive liver disease and highlights the diagnostic and prognostic potential of sEV-miRNA in ACLF while also establishing downstream gene targets.

Keywords: ACLF; EV; EV-miRNA; acute-on-chronic; cirrhosis; exosome.

Abstract

Grants and funding