The ins and outs of microRNAs as biomarkers in liver disease and transplantation

Abstract

Summary Ongoing research is being conducted in the field of transplantation to discover novel, noninvasive biomarkers for assessment of graft quality before transplantation and monitoring of graft injury after transplantation. MicroRNAs (miRNAs) are among the most promising in this field. MiRNAs are small noncoding RNAs that function as important regulators of gene expression in response to cellular stress and disease. An advantage that makes miRNAs attractive candidates for biomarker research is their fast release from cells in response to stress and injury, which can occur via different routes. In the context of liver transplantation (LT), noninvasive measurement and stability of extracellular miRNAs in blood, bile, and graft perfusates has been linked to cell‐type specific injury and early graft outcome following LT. Furthermore, specific intrahepatic miRNA expression patterns have been associated with graft survival and recurrent disease, like hepatitis C virus‐related fibrosis and hepatocellular carcinoma. Therefore, miRNAs with strong predictive value and high sensitivity and specificity might be successfully applied to assess hepatic injury and to diagnose (recurrent) liver disease before, during and after LT. In this review, the current features and future prospects of miRNAs as biomarkers in and out of the liver are discussed.

Polarized release of hepatic microRNAs into bile and serum in response to cellular injury and impaired liver function

“…Because of their cell-type abundancy, extracellular miRNAs are increasingly being investigated as non-invasive biomarkers in serum for various liver diseases (7,15). Recently, in concordance with other human and animal studies (8,9,16), our team has demonstrated the specific release of hepatocyte-derived miRNAs (HDmiRs) in blood during liver injury, chronic hepatitis C infection and acute rejection after liver transplantation (LT) (17,18).…”

The release of microRNA‐122 during liver preservation is associated with early allograft dysfunction and graft survival after transplantation

“…In the search for viable biomarkers, microRNAs (miRNAs) have gained interest due to their low complexity, stability, and organ specificity. Many studies have shown that miRNAs released in biofluids like serum, urine, and bile can be used as sensitive and accurate biomarkers . They are associated with a variety of pathologic conditions and control many cellular processes including tissue injury and repair .…”

“…Many studies have shown that miRNAs released in biofluids like serum, urine, and bile can be used as sensitive and accurate biomarkers . They are associated with a variety of pathologic conditions and control many cellular processes including tissue injury and repair . Therefore, circulating miRNAs might be helpful contributors in the existing decision‐making models to either accept or decline a potential donor liver for transplantation in order to optimize graft and patient survival.…”

Cell‐free microRNAs as early predictors of graft viability during ex vivo normothermic machine perfusion of human donor livers

“…They can down‐regulate certain processes by preventing translation of messenger RNA (mRNA) into functional proteins whereas others upregulate other cellular functions . Several studies have recently investigated the release of miRs in relation to cellular injury resulting from liver transplantation . It was shown that not only levels of released miRs differ between damaged and normal functioning hepatocytes and cholangiocytes but also that, during impaired excretory function and injury of hepatocytes, the liver shows polarized release of extracellular hepatocyte‐derived miRs (HDmiRs) and cholangiocyte‐derived miRs (CDmiRs) into both bile and serum, suggesting active rather than passive underlying release mechanisms …”

“…9 Several studies have recently investigated the release of miRs in relation to cellular injury resulting from liver transplantation. [10][11][12][13] It was shown that not only levels of released miRs differ between damaged and normal functioning hepatocytes and cholangiocytes but also that, during impaired excretory function and injury of hepatocytes, the liver shows polarized release of extracellular hepatocyte-derived miRs (HDmiRs) and cholangiocyte-derived miRs (CDmiRs) into both bile and serum, suggesting active rather than passive underlying release mechanisms. 14 The aim of the current study was to assess whether miRs in the perfusate and bile of normothermically perfused liver grafts correlate with, and are predictive of, hepatocellular and cholangiocellular injury and liver function as measured by currently available indicators and classic markers.…”