Bile extracellular vesicles from end-stage liver disease patients show altered microRNA content

Abstract

Background: Extracellular vesicles (EVs) have recently attracted attention as novel diagnostic biomarkers and therapeutic tools. Several reports have correlated blood EVs with liver diseases. However, blood EVs do not re ect the liver state as it contains other systemically circulating EVs. Therefore, we focused on bile EVs, which are secreted directly from the liver, for identi cation of potential biomarkers of liver failure. Methods: Bile samples were collected from liver transplant recipients (n = 21) diagnosed with end-stage liver disease (ESLD) and donors (normal liver, NL; n = 18) during transplantation. Bile EVs were extracted using ultracentrifugation.Results: Nanoparticle tracking analysis showed that bile EV concentration was signi cantly higher in recipients than in donors. Among recipients, bile EV concentration was remarkably higher in those with hepatocellular carcinoma. Next-generation sequencing revealed 461 and 465 types of microRNAs (miRNAs) in donor and recipient bile EVs, respectively, with no signi cant difference in diversity between the groups. Among 43 high-expression miRNAs, the expression of 86.0% of the miRNAs was higher in the bile EVs of recipients than in those of donors. Quantitative PCR validation showed that the levels of miR-17, miR-92a, miR-25, miR-423, and miR-451a signi cantly increased in bile EVs of recipients. Levels of miR-17 were remarkably higher in recipients with alcoholic ESLD.Conclusions: Secretion of EVs into the bile and their miRNA content increase in the ESLD state. Additionally, miRNA levels in bile EVs are not correlated with those in serum EVs. Bile EVs could be promising novel biomarkers for liver diseases.

Salivary Exosomes: From Waste to Promising Periodontitis Treatment

“…The detached blebs are called apoptotic bodies ( Rilla et al, 2019 ). Previous literature reported the detection of EVs from a variety of body fluids, e.g., bile ( Nakashiki et al, 2021 ), saliva ( Comfort et al, 2021 ), semen, blood ( Vojtech et al, 2019 ), breast milk ( Jiang et al, 2021 ), synovial fluid ( Mustonen et al, 2021 ), urine ( Blijdorp et al, 2021 ), and ascites ( Bortot et al, 2021 ). Generally, these EVs are composed of nucleic acids [e.g., microRNAs ( Nakashiki et al, 2021 )], proteins ( Bortot et al, 2021 ), lipids ( Skotland et al, 2020 ), and signaling molecules ( Vojtech et al, 2019 ).…”

Nucleic acid biomarkers to assess graft injury after liver transplantation

“… miR-122 48 ⇧ 🅢  miR-17 60 ⇧ 🅑  miR-107 60 ⇧ 🅣  miR-192 61 ⇧ 🅢  miR-30a 61 ⇧ 🅢  miR-155 61,62 ⇧ 🅢  miR-103 63 ⇧ 🅣  miR-34a 64 ⇧ 🅣  miR-182 65 ⇧ 🅢  miR-27a 66 ⇧ 🅢  miR-212 67 ⇧ 🅣  miR-291b 68 ⇧ 🅣  miR-223 69 ⇧ 🅢…”

“…Table 1 summarises the differentially expressed miRNAs found to be associated with acute rejection, HCV, alcohol-related liver disease, non-alcoholic fatty liver disease, hepatocellular carcinoma (HCC), or drug-mediated hepatoxicity. [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] , [78] , [79] Of note, miR-122, miR-34a, miR-223, miR-192, miR-885-5p, miR-155, and miR-21 were related to 3 or more of these conditions, demonstrating their broad potential to assess multiple forms of liver injury. Mir-122 is the only miRNA that was found to be associated with each of these conditions.…”

Role of Small Extracellular Vesicles in Liver Diseases: Pathogenesis, Diagnosis, and Treatment

“…Various studies support the potential use of sEV cargos for the diagnosis of liver fibrosis and liver failure (Table 2). 41,[65][66][67][68][69][70][71] miR-500 levels have been assayed in the circulating exosomes of patients with early and advanced stages of fibrosis. The exosomal miR-500 level was significantly higher in patients with advanced fibrosis than in patients at an early stage, suggesting the diagnostic value of exosomal miR-500 for advanced liver fibrosis.…”

“…The exosomal miR-500 level was significantly higher in patients with advanced fibrosis than in patients at an early stage, suggesting the diagnostic value of exosomal miR-500 for advanced liver fibrosis. 41 Nakashiki et al 65 found that the content of miRNA in bile sEVs was altered in patients with end-stage liver disease, and that the miRNA level was inconsistent with that in serum EVs. The study indicates the differential expression of miRNAs in bile sEVs between liver failure cells and normal cells may have high clinical diagnostic value.…”