Polarized release of hepatic micro<scp>RNA</scp>s into bile and serum in response to cellular injury and impaired liver function

Verhoeven, Cornelia J.; Farid, Waqar R. R.; Roest, Henk P.; Ramakrishnaiah, Vedashree; Ruiter, Petra E. de; Jonge, Jeroen de; Kwekkeboom, Jaap; Metselaar, Herold J.; Tilanus, Hugo W.; Kazemier, Geert; IJzermans, Jan N.M.; Laan, Luc J. W. van der

doi:10.1111/liv.12955

Cited by 15 publications

(34 citation statements)

References 44 publications

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“…In the present study, CDmiR‐222 levels in both perfusate and bile correlated strongly and positively with hepato‐cholangiocellular injury, and, in bile, with cholangiocyte function. These results are in concordance with a previous study showing that higher CDmiR‐222 levels in bile were associated with high hepatocyte injury and poor hepatocyte excretory function . The finding that both miRs were excreted into bile and strongly correlated with cellular excretory function, has been, as already mentioned, described previously …”

Section: Discussionsupporting

confidence: 93%

“…In addition to being present in perfusate, HDmiR‐122 is also present in bile. HDmiR‐122 was present in bile of patients after liver transplantation and levels decrease upon episodes of liver injury . We confirm these findings in this study, with higher levels of HDmiR‐122 in bile from livers with higher AST levels.…”

Section: Discussionsupporting

confidence: 88%

“…Studies have shown that HDmiR‐122 levels in graft preservation fluid are higher in DCD grafts and in livers that went on to develop EAD and NAS . Higher HDmiR‐122 levels in perfusate were also measured in a porcine DCD NMP model with increasing warm ischemia times .…”

Section: Discussionmentioning

confidence: 95%

“…Although not as extensively studied as HDmiR‐122, CDmiR‐222 was shown to be abundantly expressed in biliary epithelium . Elevated levels have been reported in serum of patients with primary sclerosing cholangitis, in tissue of hepatocellular carcinoma and in primary colorectal cancer lesions with liver metastases .…”

Section: Discussionmentioning

confidence: 99%

“…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 …”

Section: Introductionmentioning

confidence: 99%

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

Matton

Selten

Roest

et al. 2020

Clinical Transplantation

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Background Cell‐free microRNAs (miRs) have emerged as early and sensitive biomarkers for tissue injury and function. This study aimed to investigate whether the release of hepatocyte‐derived microRNAs (HDmiRs) and cholangiocyte‐derived miRs (CDmiRs) correlates with hepato‐cholangiocellular injury and function during oxygenated, normothermic machine perfusion (NMP) of human liver grafts. Methods Donor livers (n = 12), declined for transplantation, were subjected to oxygenated NMP (6 hours) after a period of static cold storage (median 544 minutes (IQR 421‐674)). Perfusate and bile samples were analyzed by qRT‐PCR for HDmiR‐122 and CDmiR‐222. Spearman correlations were performed between miR levels and currently available indicators and classic markers. Results Both HDmiR‐122 and CDmiR‐222 levels in perfusate at 30 minutes of NMP strongly correlated with hepatocyte injury (peak perfusate AST) and cholangiocyte injury (peak biliary LDH). In bile, only CDmiR‐222 correlated with these injury markers. For hepato‐cholangiocellular function, both miRs in perfusate correlated with total bilirubin, while HDmiR‐122 (in perfusate) and CDmiR‐222 (in bile) correlated with bicarbonate secretion. Both the relative ratio of HDmiR‐122/CDmiR‐222 and AST in perfusate at 30 minutes significantly correlated with cumulative bile production, but only the relative ratio was predictive of histopathological injury after 6 hours NMP. Conclusion Early levels of HDmiR‐122 and CDmiR‐222, in perfusate and/or bile, are predictive of excretory functions and hepato‐cholangiocellular injury after 6 hours NMP. These miRs may represent new biomarkers for graft viability and function during machine perfusion.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Matton

Selten

Roest

et al. 2020

Clinical Transplantation

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

et al. 2017

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Early allograft dysfunction (EAD) after liver transplantation (LT) is associated with inferior graft survival. EAD is more prevalent in grafts from donation after circulatory death (DCD). However, accurate prediction of liver function remains difficult because of the lack of specific biomarkers. Recent experimental and clinical studies highlight the potential of hepatocyte-derived microRNAs (miRNAs) as sensitive, stable, and specific biomarkers of liver injury. The aim of this study was to determine whether miRNAs in graft preservation fluid are predictive for EAD after clinical LT and in an experimental DCD model. Graft preservation solutions of 83 liver grafts at the end of cold ischemia were analyzed for miRNAs by reverse transcription polymerase chain reaction. Of these grafts, 42% developed EAD after transplantation. Results were verified in pig livers (n = 36) exposed to different lengths of warm ischemia time (WIT). The absolute miR-122 levels and miR-122/miR-222 ratios in preservation fluids were significantly higher in DCD grafts (P = 0.001) and grafts developing EAD (P = 0.004). In concordance, the miR-122/miR-222 ratios in perfusion fluid correlate with serum transaminase levels within the first 24 hours after transplantation. Longterm graft survival was significantly diminished in grafts with high miR-122/miR-222 ratios (P = 0.02). In the porcine DCD model, increased WIT lead to higher absolute miR-122 levels and relative miR-122/miR-222 ratios in graft perfusion fluid (P = 0.01 and P = 0.02, respectively). High miR-122/miR-222 ratios in pig livers were also associated with high aspartate aminotransferase levels after warm oxygenated reperfusion. In conclusion, both absolute and relative miR-122 levels in graft preservation solution are associated with DCD, EAD, and early graft loss after LT. As shown in a porcine DCD model, miRNA release correlated with the length of WITs. Liver Transplantation 23 946-956 2017 AASLD.

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Bile Composition as a Diagnostic and Prognostic Tool in Liver Transplantation

2020

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Bile secretion and composition reflects the functional status of hepatocytes and cholangiocytes. Bile composition can have a role in the assessment of donor grafts before implantation in the recipient. In addition, changes in bile composition after liver transplantation can serve as a diagnostic and prognostic tool to predict posttransplant complications, such as primary nonfunction, acute cellular rejection, or nonanastomotic biliary strictures. With the popularization of liver machine perfusion preservation in the clinical setting, there is a revisited interest in biliary biomarkers to assess graft viability before implantation. This review discusses current literature on biliary biomarkers that could predict or assess liver graft and bile duct viability. Bile composition offers an exciting and novel perspective in the search for reliable hepatocyte and cholangiocyte viability biomarkers.

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

Abstract: During impaired excretory function and injury, the liver shows polarized release of extracellular HDmiRs and CDmiRs. This sheds new light on the biology of hepatic miRNA release which is relevant for the interpretation of hepatic miRNAs as biomarkers.

Cited by 15 publications

References 44 publications

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

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

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

Bile Composition as a Diagnostic and Prognostic Tool in Liver Transplantation

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