Hepatocyte-derived microRNAs as serum biomarkers of hepatic injury and rejection after liver transplantation

Abstract

Recent animal and human studies have highlighted the potential of hepatocyte-derived microRNAs (HDmiRs) in serum as early, stable, sensitive, and specific biomarkers of liver injury. Their usefulness in human liver transplantation, however, has not been addressed. The aim of this study was to investigate serum HDmiRs as markers of hepatic injury and rejection in liver transplantation. Serum samples from healthy controls and liver transplant recipients (n ¼ 107) and peritransplant liver allograft biopsy samples (n ¼ 45) were analyzed via the real-time polymerase chain reaction quantification of HDmiRs (miR-122, miR-148a, and miR-194). The expression of miR-122 and miR-148a in liver tissue was significantly reduced with prolonged graft warm ischemia times. Conversely, the serum levels of these HDmiRs were elevated in patients with liver injury and positively correlated with aminotransferase levels. HDmiRs appear to be very sensitive because patients with normal aminotransferase values (<50 IU/L) had 6-to 17-fold higher HDmiR levels in comparison with healthy controls (P < 0.005). During an episode of acute rejection, serum HDmiRs were elevated up to 20-fold, and their levels appeared to rise earlier than aminotransferase levels. HDmiRs in serum were stable during repeated freezing and thawing. In conclusion, this study shows that liver injury is associated with the release of HDmiRs into the circulation. HDmiRs are promising candidates as early, stable, and sensitive biomarkers of rejection and hepatic injury after liver transplantation.

Tissue-specific exosome biomarkers for noninvasively monitoring immunologic rejection of transplanted tissue

“…Several groups have reported on whole plasma/bodily fluid profiling of free nucleic acids and proteins as biomarker platforms for monitoring rejection, especially in the context of renal transplantation (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). But diagnostic accuracy remains a critical problem, as free nucleic acids and proteins are typically nonspecific and unstable in circulation, requiring a high steady state for reliable quantitation.…”

MicroRNAs in heart transplant recipients

“…Среди 18 микроРНК, уровни которых коррелируют с отторжением трансплантата печени, наибольшей специфичностью обладают miR-122, miR-148a и miR-194. Уровни последних в сыворот-ке крови пациентов значительно увеличиваются при отторжении печени и имеют сильную позитив-ную корреляцию с активностью аминотрансферазы, используемой в клинике в качестве диагностическо-го маркера [28]. Механизм действия miR-148 связы-вают с регуляцией кальций/кальмодулин независи-мой протеинкиназы II, которая может увеличивать продукцию провоспалительных цитокинов в ответ на активацию дендритных клеток агонистами толл-подобных рецепторов (TLR) [29].…”

Barking up the wrong tree: MicroRNAs in bile as markers for biliary complications

“…13 miRNAs derived from hepatocytes, for instance, are already elevated in the serum of recipients during episodes of acute cellular rejection well before a rise in transaminases can be detected. 14 Moreover, extracellular miRNAs are more resistant against ribonuclease activity than longer messenger RNAs at room temperature or after repeated freezethaw cycles. 12,14,15 Abbreviations: DCD, donation after circulatory death; ITBL, ischemic-type biliary lesions; LT, liver transplantation; miR, micro-RNA; miRNA, microRNA.…”