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DOI: 10.1055/a-2494-2233
Extracellular Vesicles and Micro-RNAs in Liver Disease
Funding This study was supported by the NIH R01 DK136511, Mayo Clinic Center for Biomedical Discoveries, Gilead Liver Scholar award (to E.K.) and Mayo Clinic Graduate School of Biomedical Sciences stipend (to A.M.W.).
- Alcohol-Associated Liver Disease
- Metabolic Dysfunction-Associated Steatohepatitis
- Fibrosis
- Liver Malignancies
- Viral Infection
- EV-Associated miRNAs as Biomarkers and Their Therapeutic Potential
- Conclusion
- References
Abstract
Progression of liver disease is dependent on intercellular signaling, including those mediated by extracellular vesicles (EVs). Within these EVs, microRNAs (miRNAs) are packaged to selectively silence gene expression in recipient cells for upregulating or downregulating a specific pathway. Injured hepatocytes secrete EV-associated miRNAs which can be taken up by liver sinusoidal endothelial cells, immune cells, hepatic stellate cells, and other cell types. In addition, these recipient cells will secrete their own EV-associated miRNAs to propagate a response throughout the tissue and the circulation. In this review, we comment on the implications of EV-miRNAs in the progression of alcohol-associated liver disease, metabolic dysfunction-associated steatohepatitis, viral and parasitic infections, liver fibrosis, and liver malignancies. We summarize how circulating miRNAs can be used as biomarkers and the potential of utilizing EVs and miRNAs as therapeutic methods to treat liver disease.
#
Liver cells release particles, named extracellular vesicles (EVs), that are shown to play important roles in the progression of liver diseases. These EVs contain a type of short RNAs that do not code for proteins, named micro-RNAs (miRNAs). The purpose of this review is to comment key findings about the role of EV-associated miRNAs in different liver pathologies and pathological features, including alcohol-associated liver disease, metabolic dysfunction-associated steatohepatitis, liver fibrosis and cirrhosis, viral infections, and liver malignancies.
Chronic liver disease, a progressive deterioration of liver functions, affects more the 800 million people worldwide and is responsible for 2 million deaths annually.[1] [2] There is a lack of effective therapies against chronic liver diseases, leading to a need of better understanding their pathobiology. Over the last decade, it has been shown that extracellular vesicles (EVs) are some of the key drivers of liver disease progression.[3] [4] [5] EVs are nano-to-micro-sized particles important for intercellular communication, presumably released by every cell type, and delineated by a lipid bilayer.[3] [4] [5] [6] Other types of particles released by cells include exomeres and supermeres.[7] [8] However, they are not delineated by a membrane and thus are considered as nonvesicular entities,[6] which are out of the scope of this review. Based on the biogenesis pathway, there are two main types of EVs released by healthy cells, microvesicles, and exosomes. Microvesicles are formed by outward budding of the plasma membrane, while exosomes originate from inward budding of the membrane of multivesicular bodies (MVBs).[6] [9] Current isolation methods have led to another classification that separates EVs based on size. There are two main size-based populations of EVs, small EVs measuring less than 200 nm, and large EVs measuring up to 1 μm. However, there is no consensus on the cutoff sizes for each population and small EVs usually are a mixture of exosomes and microvesicles.[6]
EVs carry a multitude of biological molecules, including micro RNAs (miRNAs).[3] [4] [5] [6] Since their discovery in Caenorhabditis elegans, miRNAs have been identified as crucial posttranscriptional regulators of mRNA stability and subsequent protein expression.[10] Some current prediction tools to identify RNAs that can be targeted by miRNA include TargetScan (targetscan.org), miRDB (mirdb.org), and RNA22 (cm.jefferson.edu/rna22/).[11] [12] [13] [14] MiRNAs are conserved antisense single-stranded sequences of 22 nucleotides that bind to messenger RNAs (mRNAs) to silence their expression through inducing their degradation.[10] [15] [16] [17]The synthesis of miRNAs starts with the transcription of DNA sequences into RNA hairpin precursors, which are later matured by the nucleases Dicer, transactivation response element RNA-binding protein, and argonaute 2 (AGO2).[15] [16] [17] The sorting of mature miRNAs into MVBs and subsequent EVs seems to be a selective process for specific miRNAs. For example, miRNA sorting into EVs is facilitated by Y-box binding protein 1 (YB-1) for miR-223 and heterogeneous nuclear ribonucleoproteins A2/B1 (HNRPA2B1) for miR-198.[18] [19] [20] In addition, the nuclease that facilitates miRNA maturation, Ago2, has been shown to also interact with MVBs and enrich them with miR-16 and let-7a, leading to EVs enriched with Ago2–miRNA complexes.[21] [22] This leads to the regulation of various cellular processes, such as cell cycle, inflammation, stress response, differentiation, and migration.[10] This review encompasses the role of miRNA-enriched EVs during various liver injuries, including alcohol-associated liver disease (ALD), metabolic-associated steatohepatitis (MASH), fibrosis, carcinogenesis, viral hepatitis, as well as a perspective regarding EV-based biomarkers and therapeutics.
Alcohol-Associated Liver Disease
Alcohol consumption persist as a global cause of liver disease.[23] Hepatocytes are directly injured by the oxidation of ethanol, which disrupts NAD+ redox potential and promotes fatty acid synthesis.[24] Sequential consequences of ethanol oxidation include the accumulation of lipid droplets in the hepatocytes and the secretion of proinflammatory signals to recruit immune cells.[25] Inflammation is a key feature of alcohol-associated liver disease. EVs and miRNA have been shown to be essential mediators of cell–cell communication during inflammation, particularly by promoting macrophage polarization ([Fig. 1]).[3] [4] [23] [26] Plasma from patients with ALD showed an increase in EV number and enrichment of these EVs with a specific miRNA barcode, including let-7f, miR-29a, and miR-340.[27] Similarly to human ALD, mouse models of ALD also showed an increase of circulating EVs.[28] In addition, circulating EVs from alcohol-fed mice were enriched with miR-192 and miR-30a,[29] which when administered intravenously into alcohol-naïve mice increased miR-192 levels in hepatocytes and inflammatory macrophage accumulation in the liver.[28] Accumulation of inflammatory macrophages in the liver is also promoted by increased expression of miR-155,[30] which stabilizes TNFα mRNA.[31] Moreover, miR-155 targets LAMP1 and LAMP2, which in turn increases EV release in hepatocytes and macrophages during alcohol injury.[32] The content of these miR-155-dependent EVs through which they may promote inflammation and steatosis remains to be studied. In line with these findings, in vivo intragastric infusion model of ALD was associated with the release of hepatocyte-derived EVs that contained a specific miRNA barcode, which was predicted to target genes involved in inflammation and cancer.[27] This barcode included let7f, miR-29a, and miR-340, which were also increased in patients with ambulatory mild ALD as compared with healthy controls.[27] In addition to hepatocyte-derived EVs, in vitro analysis suggested that exposure to alcohol promotes the release of EVs by human monocytes.[33] Moreover, these EVs derived from ethanol-stimulated monocytes contained miR-27a, which induced the polarization of naïve monocytes into M2 macrophages expressing profibrotic TGFβ.[33] However, the molecular mechanism by which miR-27a induces these phenotypic changes remains unclear. In addition to being transported via EVs, alcohol-associated miRNA can also affect EV release. In a recent study, miR-122 and miR-192 levels were decreased in hepatocytes treated with alcohol in vitro, a treatment that is recognized to increase EV release.[25] Congruently, miR-192 inhibition in human hepatoma cells significantly increased EV secretion from these cells.[25] Despite numerous efforts on discovering the EV-associated miRNAs involved in ALD and predicting their targets, the mechanisms used by these miRNAs to modify EV release in the cell of origin and molecular signaling in the recipient cells deserve further investigation.
#
Metabolic Dysfunction-Associated Steatohepatitis
Hepatic steatosis unassociated with alcohol consumption is referred to as metabolic dysfunction-associated steatotic liver disease, or metabolic dysfunction-associated steatotic liver disease (MASLD), and affects 30% of adults worldwide.[34] [35] MASLD hallmarked by hepatocellular injury, hepatic inflammation, and progressive liver fibrosis is referred to as metabolic dysfunction-associated steatohepatitis (MASH), previously termed nonalcoholic steatohepatitis.[35] [36] EVs and miRNAs have been shown to play pivotal roles during the pathobiology of MASH ([Fig. 1]).[37] [38] [39] In vitro studies have demonstrated that during lipotoxic stress, hepatocytes secrete EV-associated miR-128-3p, which targets peroxisome proliferator-activated receptor gamma (PPAR-γ) in hepatic stellate cells (HSCs) and inhibits HSC activation.[40] Furthermore, EV-associate miR-199a-5p delivery in mice targets the 3′ untranslated region of macrophage stimulating 1 (MST1) in the liver and aggravates lipid accumulation in hepatocytes.[41] In turn, steatotic hepatocytes release miR-1-enriched EVs, which increase nuclear factor-kappa B (NF-κB) activity in recipient endothelial cells and promote the expression of proinflammatory molecules in vitro.[42] A hallmark of MASH is the accumulation of inflammatory cells, including neutrophils, around the lipotoxic hepatocytes, which is believed to promote liver injury.[43] However, inflammatory cells can be beneficial to the liver. Indeed, neutrophil-derived EVs enriched with miR-223 reduce inflammatory and fibrogenic gene programs in recipient hepatocytes in a low-density lipoprotein receptor fashion.[44] These studies suggest that the progression of MASH is the result of the ration between detrimental versus beneficial signals, including miRNA-enriched EVs, which occur simultaneously and deserve more in-depth consideration. MiR-122 is one of the most abundant and studied miRNAs in the adult liver, playing a crucial role in liver homeostasis, the regulation of cholesterol, and fatty acid metabolism.[45] [46] However, miR-122 has been reported to exert beneficial and detrimental roles during MASH. Circulating EVs in mice with metabolic disease are enriched with miR-122 and miR-192.[47] These EVs, when transplanted into lean mice, promote glucose intolerance and hepatic steatosis.[47] Nevertheless, reported targets of miR-122 include Agpat1, Dgat1, CPEB1, and Sirt, which are involved in lipid metabolism.[48] [49] [50] Inhibiting miR-122 expression leads to triglyceride accumulation in the liver,[48] suggesting a beneficial role for miR-122 in MASH. The discrepancy between the aforementioned studies might be due to the distinct roles of intracellular versus EV-associated miR-122, as well as 5p versus 3p sequences, leading to the need of a deeper investigation of miR-122 during MASLD and MASH.
#
Fibrosis
Cirrhosis is a chronic liver disease where severe scarring diminishes liver function.[51] Development of scarring in the liver is denoted by the progression of fibrosis stages.[51] Liver injury induces the activation of HSCs, including cell proliferation, migration, and matrix deposition in response to platelet-derived growth factor (PDGF), transforming growth factor beta (TGFβ), connective tissue growth factor (CTGF), and other growth factors and cytokines.[51] In addition to the canonical PDGF and TGF stimuli, HSC can also be activated by EVs.[3] [4] Indeed, EVs derived from donor HSCs activated with PDGF are enriched with fibrogenic proteins and they promote recipient HSC migration and liver fibrosis in mice.[52] [53] [54] In addition to proteins, fibrosis and HSC activation have been shown to be regulated by miRNAs and EV-associated miRNAs ([Fig. 2]).[39] [55] [56] [57] More specifically, quiescent HSCs release EVs enriched with miR-199a-5p and miR-214 that target the fibrogenic connective tissue growth factor in activated HSCs,[55] [58] suggesting a beneficial role for quiescent HSC-derived EVs in liver fibrosis. EVs derived from bone marrow mesenchymal stem cells enriched with miR-192-5p also seem to be beneficial as they inhibit HSC activation.[59] Congruently, EVs derived from adipose mesenchymal stem cells contain miR-223, which target E2F1 transcription factor in hepatocytes to attenuate fibrosis.[60] In addition to mesenchymal stem cells, IL6-stimulated macrophages release EVs containing miR-223 that disrupt the profibrotic tafazzin expression in recipient hepatocytes.[61] On the other hand, ethanol-stressed hepatocytes release EV-associated miR-423-5p to inhibit HSC activation.[62] However, since stressed hepatocytes are recognized to promote disease progression, further studies are needed to understand whether there is a subpopulation of stressed hepatocytes that can be beneficial to liver injury, notably by secreting EV-associated miR-423-5p.
Injured hepatocytes isolated from an alcoholic hepatitis mouse model secrete EVs enriched with specific miRNAs, such as let-7i-5p, let-7f-5p, and let-7a-5p, and promote primary mouse HSC activation in vitro.[63] These results were in line with a previous study demonstrating that lipotoxic palmitic acid-treated Huh7 cells (hepatocyte cell line) release EVs enriched with miR-122 and miR-192, which promote LX2 (immortalized HSCs) activation in vitro.[64] Lipotoxic hepatocytes release EVs that shuttle miR-128-3p into recipient HSCs in vitro to target PPARγ and subsequently increase HSC activation.[40] In addition to the hepatocytes, lipopolysaccharide-treated THP-1 macrophages release EVs that contain miR-103-3p and enhance LX2 activation and fibrogenesis.[65] However, these studies need further investigation by utilizing primary cells as well as knockdown/rescue experiments to confirm the role of EV-enriched miRNA on HSC activation. In a more recent study, the expression of miR-199a-5P in LX2 increased the expression of fibrogenic markers such as Col1 and αSMA. In addition, LX2-derived EVs transporting miR-199a-5P decreased sirtuin 1 expression and subsequently increased epithelial cell proliferation and senescence.[66]
Injuries to the liver by pathogens also trigger HSC activation and fibrogenesis. Specifically, eggs of parasitic schistosomula release miR-33-enriched EVs to promote in vitro αSMA and collagen 1 expression in LX2 and liver fibrosis in mice.[67] Female Schistosoma japonicum, a parasite that needs collagen for reproduction, secrete EVs containing sja-miR-2162 to activate HSCs by targeting TGF beta receptor 3.[68] In line with these studies, Clonorchis sinensis-derived EVs contain Csi-let-7a-5p, which induces biliary fibrosis.[69] In summary, these studies advance our understanding of the beneficial as well as detrimental effects of specific EV-associated miRNAs. It would be interesting to understand whether targeting several EV-associated miRNAs simultaneously could have a synergetic effect on the behavior of HSCs during liver fibrosis.
#
Liver Malignancies
Primary liver cancers are aggressive malignancies with abysmal survival rates across all Surveillance, Epidemiology, and End Results stages. The two most common primary liver cancers are hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Cancer-derived EVs have been shown to have protumorigenic effects in liver carcinogenesis ([Fig. 2]).[70] EV-associated miRNAs persist as intriguing components of primary HCC as they are utilized to promote proliferation, escape of the immune system, and recruiting cells to the tumor microenvironment.[71] HCC cells can release EVs that differ in both RNA and protein content from their cells of origin.[72] More specifically, these EVs contain an exclusive subset of miRNAs, including miR-584, miR-517c, miR-378, and others, regulate transforming growth factor β activated kinase-1 (TAK1) in recipient cells to promote transformed cell growth.[72] In line with these findings, miRNA-155 in HCC cell-derived EVs promotes tumor growth in an HCC xenograft model in mice by suppression of cell proliferation agonists phosphatase and tensin homolog (PTEN).[73] To desensitize the immune system, HCC-derived EVs package miR-146a-5p and miR-23a-3p to desensitize or exhaust T-cells and regulate programmed death ligand 1 expression in macrophages, respectively.[74] [75] Interestingly, EVs produced by HCC cells were found to inactivate tumor suppressive miRNA via trafficking of circular RNA to act as sponges for free cytosolic miRNA.[76] For example, a recent study has shown that HCC releases exosomal circCCAR1 to act as a sponge for miR-127-5p to facilitate CD8+ T-cell dysfunction.[77] In addition, analysis of circulating EVs in HCC patients revealed that circGSE1, another circular RNA, inhibited T-cell mediated immune response by acting as a sponge for miR-324-5p.[78] [79] In addition to enhancing cancer cell proliferation and immune cell escape, to produce an efficient tumor microenvironment, other cell types can be reprogrammed by the tumor. In this regard, HCC cells under hypoxic conditions release EVs containing miR-155, which promote in vitro tube formation in human umbilical vein endothelial cells (HUVECs).[80] In addition, cancer cells can reprogram nonparenchymal cells such as HSCs into extracellular matrix-producing cancer-associated fibroblasts (CAFs), which are key drivers of advanced malignancies.[3] [81] [82] Metastatic HCC cells secrete EVs containing miR-1247-3p that directly targets beta-1,4-galactosyltransferase 3 (B4GALT3), leading to the activation of β1-integrin-NF-κB signaling in CAFs.[83] Moreover, HCC-derived EVs that contain miR-21 reprogram HSCs into CAFs via upregulation of phosphoinositide-dependent kinase 1/Ak strain transforming (PDK1/AKT) signaling, which in turn support HCC progression through releasing vascular endothelial growth factor, matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), basic fibroblast growth factor (bFGF), and TGF-β.[84] [85] However, HSCs also release beneficial EVs, such as miR-335-5p-enriched EVs that induce HCC tumor shrinkage in vivo,[86] underlying the need of studying the heterogeneity of HSCs and their respective EVs.
CCA, although an uncommon cancer, is the second most common primary liver cancer. Recently, it has been shown that EVs derived from gemcitabine-resistant CCA cells contain miR-141-3p, which increased the resistance of recipient CCA cells.[87] In line with this study, EV-associated miR-182-5p promoted resistance to gemcitabine and cisplatin through supporting angiogenesis.[88] Moreover, EV-associated miR-183-5p derived from CCA cells upregulated programmed death-ligand 1 (PD-L1)-expressing macrophages to enhance cancer progression through the PTEN/AKT/PD-L1 pathway.[89] These studies suggest that EV-associated miRNAs have immunomodulatory, proangiogenic, and chemotherapy resistance roles.
In addition to primary liver cancers, the liver hosts the metastases of other organ cancers. Pancreatic cancers can spread to the liver in about 80% of the cases.[90] The metastatic potential may be aided through the release of pancreatic cancer-derived EV-associated miR-4488 or tumor-associated macrophage-derived EV-miR-202-5p and miR-142-5p.[91] [92] [93] Furthermore, bone marrow-derived cells produce EVs with miRNA-92a to activate HSCs in premetastatic niche in lung cancer.[94] Understanding the function of EV-associated miRNAs that are prevalent in liver malignancies will provide new insight into cancer pathogenesis and drug resistance.
#
Viral Infection
Viral infection in the liver is a potent driver of hepatic injury with the most prevalent strains being hepatitis B and C. Indeed, long-term infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), which have a tropism for hepatocytes, leads to chronic hepatitis and increased risk to develop liver failure, liver cancer, or cirrhosis.[95] It has been shown that downregulation of miR-172-5p and miR-1285-5p in serum EVs from patients infected with HBV helps to predict the progression toward chronic hepatitis B ([Fig. 2]).[96] In vitro studies demonstrate that hepatocytes hosting an active HBV replication release EVs that are enriched in several miRNAs including has-miR-4514, has-miR-6133, and has-miR-6970-5p.[97] However, the role of these secreted miRNAs in HBV infection remains to be studied. In addition to their potential as biomarkers,[98] EV-associated miRNAs can modulate the immune response to HBV. In vitro HBV infection of hepatocytes increased the expression of HBV-miR-3.[99] EVs enriched with HBV-miR-3 induced a proinflammatory phenotype in macrophages, which restrained HBV replication,[99] a mechanism that may be used by the host against viral infection. In line with these findings, interferon α (IFNα)-mediated miR-193a-5p, miR-25–5p, and miR-574–5p enrichment and miR-27b-3p decrease in monocyte-derived EVs disrupted HBV replication.[100] [101] [102] HCV is another viral strain that can cause chronic hepatitis. HCV infection in patients has been found to correlate with an increase in circulating miR-192-5p and miR-29a, a mature variant of miR-29.[103] [104] However, miR-29-enriched EVs released from toll-like receptor 3 (TLR3)-activated macrophages are beneficial as they inhibit HCV replication in recipient hepatocytes in vitro.[105] Thus, a deeper study of the role of each of the mature variants of miR-29 during HCV infection is needed. To promote its replication, HCV utilizes the EV biogenesis machinery and promotes the release of HCV RNA through EVs, which are partially resistant to antibody neutralization and shedding light on a possible mechanism of immune evasion.[106] Congruently, plasma EVs from patients infected with HCV are enriched with miR-122-5p and miR-146a-5p, which target key components of immunoregulatory signaling pathways and antiviral interferon-mediated responses.[107] In addition to the immunomodulatory effect, EVs derived from HCV-infected hepatocytes have profibrotic effects as they carry miR-19a, which promotes the expression of fibrogenic genes in recipient HSCs.[108] Although these studies have demonstrated how viruses utilize EVs to modulate host cell behavior, further investigations are needed to understand the molecular mechanisms of miRNAs transfer and release in the recipient cells.
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EV-Associated miRNAs as Biomarkers and Their Therapeutic Potential
EVs hold potential as biomarkers because they (1) are abundant in physiological fluids, (2) can be obtained with minimal invasion, and (3) are ideal for longitudinal clinical and preclinical studies ([Table 1]).[4] [109] Steatotic liver diseases present circulating EVs enriched with miR-155 and miR-122, in mice and humans.[100] [110] Let7f, miR-29a, and miR-340 are enriched in circulating EVs in murine models of alcohol-associated steatohepatitis (ASH), but not in other models of liver injury.[27] These data were also confirmed in patients with ASH,[27] suggesting the potential to use the combination of these three EV-associated miRNAs for the diagnosis of ASH. A recent study reports that miR-103, miR-25, and miR-92a are enriched in circulating EVs from patients with MASLD and high-fat diet-fed mice as compared with respective healthy controls.[111] Moreover, the decrease of EV-associated miR-411-5p expression in sera of patients with MASH correlates with HSC activation during MASH,[112] suggesting that circulating miR-411-5p might be a potential biomarker for MASH-associated fibrosis. Activation of HSCs can be quantified by an array of circulating miRNAs to access progression of liver fibrosis. Blood EVs enriched for miR-103-3p in patients have been associated with activation of HSCs and liver fibrosis progression.[65] In a recent study, enhanced expression of circulating miR-146b and miR-214 is proposed as a biomarker for liver fibrosis.[113] MiR-29 is the most thoroughly investigated miRNA-family in HSCs and its expression is attenuated during HSC activation and liver fibrosis in vivo.[114] [115] It would be interesting to investigate the levels of circulating EV-associated miR-29 in different etiologies of liver injury. During early-stage fibrosis associated with HBV or HCV, EV-associated miR-122, miR-150, miR-192, miR-200b, and miR-92a were decreased, while in total plasma miR-122 and miR-200b expression was upregulated,[116] suggesting that the analysis of both total plasma and circulating EVs can give a more accurate information regarding liver injury. In regard to the detection of HCC, several EV-associated miRNAs have been reported, such as increased expression of miR-10b-5p, miR-221-3p, miR-223-3p, and miR-21-5p and decreased presence of miR-101, miR-106b, miR-122, miR-195.[117] Studies with samples from patients with CCA showed increased levels of circulating miR-191, miR-486-3p, miR-1274b, miR-16, miR-484, and others.[118] Nevertheless, despite the numerous advantages of utilizing EVs and their respective miRNA cargos as biomarkers, several challenges must be addressed such as standardization of EV collection and storage methods, variability among individuals including gender and ethnicity, as well as EV heterogeneity during stages of diseases.[119] Indeed, the type of biospecimens, such as serum, plasma, saliva, or urine, can vehicle different types of miRNA-enriched EVs. In addition, the storage conditions of EVs, including buffer and temperature, for later analysis can affect the integrity of their cargo. Finally, variability among individuals and their respective lifestyles can affect the concentration of EVs in the biospecimen as well as their cargo. Thus, standardization of the methods, stratification based on gender and ethnicity and imposing a lifestyle for a period of time prior to the EV collection might be necessary toward utilization of miRNA-enriched EVs as biomarkers. Studies of miRNA specific to a type of liver injury or a combination of circulating miRNAs and proteins through multiomics analyses might be considered for more accurate information.
|
Liver pathology |
MicroRNA |
Organism |
Application |
References |
|---|---|---|---|---|
|
ALD |
||||
|
Let7f |
Mice |
Biomarker |
[21] |
|
|
miR-29a |
Mice |
Biomarker |
[21] |
|
|
miR-340 |
Mice |
Biomarker |
[21] |
|
|
miR-155 |
Mice |
Biomarker |
||
|
miR-122 |
In vitro, hepatocytes |
Biomarker |
[104] |
|
|
miR-192 |
Mice |
Biomarker |
[23] |
|
|
miR-30a |
Mice |
Biomarker |
[23] |
|
|
miR-27a |
In vitro, monocytes |
Biomarker |
[27] |
|
|
MASH |
||||
|
miR-103 |
Patient serum |
Biomarker |
[105] |
|
|
miR-25 |
Patient serum |
Biomarker |
[105] |
|
|
miR-92a |
Patient serum |
Biomarker |
[105] |
|
|
miR-411-5p |
Patient serum |
Biomarker |
[106] |
|
|
miR-223-3p |
Mesenchymal stem cell |
MASH treatment |
[54] |
|
|
miR-128-3p |
In vitro, hepatocytes |
Biomarker |
[34] |
|
|
miR-199a-5p |
Mice |
Biomarker |
[35] |
|
|
miR-223 |
In vitro, hepatocytes |
Biomarker |
[38] |
|
|
MiR-122 |
Patient serum |
Biomarker |
||
|
miR-21 |
In vitro, hepatocytes |
Biomarker |
[36] |
|
|
miR-192 |
Mice |
Biomarker |
[41] |
|
|
Liver fibrosis |
||||
|
miR-122 |
In vitro, LX2 |
Biomarker |
||
|
miR-29a |
Mouse serum |
Biomarker |
||
|
miR-150 |
Patient serum |
Biomarker |
[110] |
|
|
miR-192 |
In vitro, LX2 |
Biomarker |
||
|
miR-200b |
Patient serum |
Biomarker |
[110] |
|
|
miR-92a |
Patient serum |
Reduce HSC activation |
||
|
miR-146b |
Patient serum |
Biomarker |
[107] |
|
|
miR-214 |
Patient serum |
Biomarker |
[107] |
|
|
miR-199a-5p |
In vitro, LX2 |
Biomarker |
[49] |
|
|
miR-214 |
In vitro, LX2 |
Biomarker |
[52] |
|
|
miR-192-5p |
In vitro, LX2 |
Reduce HSC activation |
[53] |
|
|
miR-223 |
Mice |
Reduce HSC activation |
[54] |
|
|
miR-423-5p |
In vitro, LX2 |
Reduce HSC activation |
[56] |
|
|
let-7i-5p |
Mice |
Biomarker |
[57] |
|
|
let-7f-5p |
Mice |
Biomarker |
[57] |
|
|
let-7a-5p, |
Mice |
Biomarker |
[57] |
|
|
miR-103-3p |
In vitro, LX2 |
Biomarker |
[59] |
|
|
miR-199a-5P |
In vitro, LX2 |
Biomarker |
[60] |
|
|
miR-33 |
In vitro, LX2 |
Biomarker |
[61] |
|
|
miR-128-3p |
In vitro, LX2 |
Biomarker |
[61] |
|
|
miR-92a-3p |
Mice |
Biomarker |
[117] |
|
|
miR-103-3p |
Patient serum |
Biomarker |
[59] |
|
|
HCC |
||||
|
miR-10b-5p |
Patient serum |
Biomarker |
[111] |
|
|
miR-221-3p |
Patient serum |
Biomarker |
[111] |
|
|
miR-223-3p |
Patient serum |
Biomarker |
[111] |
|
|
miR-21-5p |
Patient serum |
Biomarker |
[111] |
|
|
miR-101 |
Patient serum |
Biomarker |
[111] |
|
|
miR-106b |
Patient serum |
Biomarker |
[111] |
|
|
miR-122 |
Patient serum |
Biomarker |
[111] |
|
|
miR-195 |
Patient serum |
Biomarker |
[111] |
|
|
anti-miRNA21 |
Mice |
Immune checkpoint blockade |
[119] |
|
|
miR-584 |
In vitro, HEP3B, HEPG2 |
Biomarker |
[66] |
|
|
miR-517c |
In vitro, HEP3B, HEPG2 |
Biomarker |
[66] |
|
|
miR-378 |
In vitro, HEP3B, HEPG2 |
Biomarker |
[66] |
|
|
miRNA-155 |
In vitro, HEP3B, HEPG2 |
Biomarker |
[67] |
|
|
miR-146a-5p |
In vitro, HEP3B, HEPG2 |
Biomarker |
[68] |
|
|
miR-23a-3p |
In vitro, HEP3B, HEPG2 |
Biomarker |
[69] |
|
|
miR-127-5p |
Mice |
Biomarker |
[71] |
|
|
circGSE1, |
Mice |
Biomarker |
[71] |
|
|
circCCAR1 |
Mice |
Biomarker |
||
|
miR-324-5p |
Mice |
Biomarker |
||
|
miR-21 |
In vitro, Huh7, LX2, Huvec |
Biomarker |
||
|
miR-335-5p |
In vitro, LX2 |
Biomarker |
[80] |
|
|
miR-1247-3p |
In vitro, primary HCC cells |
Biomarker |
[77] |
|
|
CCA |
||||
|
miR-191 |
Patient serum |
Biomarker |
[112] |
|
|
miR-486-3p |
Patient serum |
Biomarker |
[112] |
|
|
miR-1274b |
Patient serum |
Biomarker |
[112] |
|
|
miR-16 |
Patient serum |
Biomarker |
[112] |
|
|
miR-484 |
Patient serum |
Biomarker |
[112] |
|
|
miR-141-3p |
In vitro, CCA cells |
Biomarker |
[81] |
|
|
miR-182-5p |
In vitro, CCA cells |
Biomarker |
[82] |
|
|
miR-183-5p |
In vitro, CCA cells |
Biomarker |
[83] |
|
|
miR-142-5p |
Patient serum |
Metastatic biomarker |
[87] |
|
|
miR-92a |
Patient serum |
Metastatic biomarker |
[88] |
|
|
miR-202-5p |
Patient serum |
Metastatic biomarker |
[86] |
|
|
miR-4488 |
Patient serum |
Metastatic biomarker |
[85] |
|
|
Viral infection |
||||
|
HBV-miR-3 |
In vitro, hepatocytes and macrophages |
HBV biomarker |
[93] |
|
|
anti-miR-122 |
mice |
HCV treatment |
[118] |
|
|
miR-172-5p |
Patient serum |
HBV biomarker |
[90] |
|
|
has-miR-4514 |
In vitro, hepatocytes |
HBV biomarker |
[91] |
|
|
has-miR-6133 |
In vitro, hepatocytes |
HBV biomarker |
[91] |
|
|
has-miR-6970-5p |
In vitro, hepatocytes |
HBV biomarker |
[91] |
|
|
miR-1285-5p |
Patient serum |
HBV biomarker |
[90] |
|
|
miR-193a-5p |
Mice |
Disrupts HBV replication |
[94] |
|
|
miR-25–5p |
Patient-derived monocytes |
Disrupts HBV replication |
[95] |
|
|
miR-574–5p |
Patient-derived monocytes |
Disrupts HBV replication |
[95] |
|
|
miR-27b-3p |
Patient-derived monocytes |
Disrupts HBV replication |
[96] |
|
|
miR-192-5p |
Patient blood |
HCV biomarker |
[97] |
|
|
miR-29a |
In vitro, primary human hepatocytes |
HCV biomarker |
||
|
miR-122-5p |
Patient plasma |
HCV biomarker |
[101] |
|
|
miR-146a-5p |
Patient plasma |
HCV biomarker |
[101] |
Abbreviations: ALD, alcohol-associated liver disease; CCA, cholangiocarcinoma; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HSC, hepatic stellate cell; MASH, metabolic-associated steatohepatitis.
EVs are also a potential therapeutic tool due to their natural structure and low immunogenicity.[120] There are nearly 471 reported EV-related clinical trials, with indications for over 200 diseases.[121] Among these trials, 91 clinical trials utilize EVs as therapeutic agents and 3 of them use either mesenchymal stem cell-derived or engineered EVs to treat liver diseases.[121] Natural or engineered EVs to transfer miRNAs has been proposed to treat liver diseases.[122] Indeed, EVs derived from induced pluripotent stem cells enriched with miR-92a-3p can be used to treat liver fibrosis as they reduce HSC activation.[123] In addition, mesenchymal stem cell-derived EVs are shown to be beneficial in MASH through delivering miR-223-3p.[60] Another interesting approach is the chemical synthesis of anti-miRNAs or antimirs, such as anti-miR-122 for HCV treatment,[124] or anti-miRNA21 for immune checkpoint blockade.[125] Enriching stem cell-derived EVs with therapeutic antimirs could have a synergetic effect on the treatment of liver disease, but their beneficial role is yet to be examined. While most of the studies propose to utilize specific miRNAs to treat a particular disease, it would be interesting to consider the possibility of administering EVs containing a signature of several miRNAs that could target a pathway or a network of molecules involved in the disease. For example, the EVs could be edited to incorporate identified miRNAs through the prediction tools, to target inflammatory pathways during MASH. However, technological limitations might impose significant constraints that, we hope, will resolve in the near future.
#
Conclusion
Previous reviews have highlighted the challenges in therapeutic application of EVs.[4] Due to the diversity of miRNA's origin and function in different etiologies, the exact role of many miRNAs identified in liver diseases remains unknown. For example, HCC cells utilize miR-29a to promote cancer cell proliferation while it inhibits collagen 1 (COL1) expression in HSCs.[126] [127] Furthermore, miRNAs circulating in the liver are also derived from other organs.[128] A prominent example is adipose derived EVs transporting miR-155 to promote insulin resistance in hepatocytes.[129] As such, therapies targeting EV-associated miRNAs must consider tissue specificity and the purpose for this miRNA in different cell types. Further research into EV-associated miRNAs is needed as they hold promise in identifying novel therapies in the dauntless efforts to cure liver disease.
#
#
Conflict of Interest
None declared.
Author Contribution
E.K. conceived and supervised the study; A.W. and E.K. wrote and revised the manuscript.
-
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Publication History
Accepted Manuscript online:
03 December 2024
Article published online:
24 December 2024
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