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  • Original Article
  • OPEN ACCESS

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases

  • Kun-Li Yin1,#,
  • Ming Li1,#,
  • Pei-Pei Song2,
  • Yu-Xin Duan1,
  • Wen-Tao Ye1,
  • Wei Tang2,
  • Norihiro Kokudo2,
  • Qiang Gao3,4,5,*  and
  • Rui Liao1,* 
 Author information
Journal of Clinical and Translational Hepatology 2023;11(2):441-451

DOI: 10.14218/JCTH.2022.00326

Abstract

Hepatic stellate cells (HSCs) play an essential role in various liver diseases, and exosomes are critical mediators of intercellular communication in local and distant microenvironments. Cellular crosstalk between HSCs and surrounding multiple tissue-resident cells promotes or inhibits the activation of HSCs. Substantial evidence has revealed that HSC-derived exosomes are involved in the occurrence and development of liver diseases through the regulation of retinoid metabolism, lipid metabolism, glucose metabolism, protein metabolism, and mitochondrial metabolism. HSC-derived exosomes are underpinned by vehicle molecules, such as mRNAs and microRNAs, that function in, and significantly affect, the processes of various liver diseases, such as acute liver injury, alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, fibrosis, and cancer. As such, numerous exosomes derived from HSCs or HSC-associated exosomes have attracted attention because of their biological roles and translational applications as potential targets for therapeutic targets. Herein, we review the pathophysiological and metabolic processes associated with HSC-derived exosomes, their roles in various liver diseases and their potential clinical application.

Keywords

Myofibroblast, Extracellular vesicle, Hepatic fibrosis, Cancer, Metabolic reprogramming, Biomarker

Introduction

Hepatic stellate cells (HSCs) account for approximately 15% of resident cells in normal liver and 30% of nonparenchymal cells.1,2 HSCs exist in the space of Disse with multiple lipid droplets rich in vitamin A present in the cytoplasm, representing the primary storage site of retinaldehyde derivatives.3 In additional, HSCs are the main cells synthesizing the extracellular matrix (ECM) and collagen in the liver. HSCs are normally quiescent (qHSCs) and do not express alpha-smooth muscle actin (α-SMA), which is a marker of activated HSCs (aHSCs).2 Numerous studies have confirmed that HSCs exhibit great heterogeneity and plasticity and facilitate fine regulatory responses to liver injury through paracrine and autocrine signals according to changes in the extracellular microenvironment.4–6

Exosomes are membranous vesicles that fuse with the cell membrane by multiple vesicles and are then released to the extracellular space. Exosomes have a diameter of 40–160 nm and they are released by all types of cells.7,8 Exosomes can be found in almost all body fluids, such as plasma,9 urine,10 cerebrospinal fluid,11 saliva,12 breast milk,13 joint fluid,14 amniotic fluid,15 and semen.16 Of note, some special proteins are found on the surface of exosome vesicles, such as HSP70, CD9, CD63, CD62, and CD81. The proteins are involved in cell adhesion and targeting and can be used as biomarkers to indirectly reflect the presence of exosomes.6 Exosomes, as heterogeneous intraluminal vesicles (ILVs), are secreted into the extracellular space by endosomal sorting complex required for transport mechanisms.8 In these complex processes, exosomes are filled with lipids, proteins, DNA, coding RNA and noncoding (nc)RNAs such as micro (mi)RNA, long noncoding (lnc)RNA, and circular (circ)RNA.17 Transfer of these active substances from tissue to body fluids in intercellular cargo contributes to the transmission of information via exosomes and subsequently affects the occurrence and development of various diseases.18

The roles of exosomes in intercellular information exchange have attracted more attention to dissect the mechanisms leading to the activation of HSCs.19,20 As a part of the liver environment, HSC-derived exosomes play an important role in the development of liver diseases.21–23 In this review, we summarize the pathophysiological and metabolic processes associated with HSC-derived exosomes, their roles in various liver diseases and their potential clinical application.

Mechanism of HSC activation

When the liver is damaged by inflammation or mechanical stimulation, fibrogenic factors, such as transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF), insulin-like growth factor, and interleukin (IL)-6, seek HSCs as the final target cells (Fig. 1). The phenotype of HSCs then changes from quiescent to activated, and these cells transform into myofibroblasts (MFBs).24–26 The concepts of “initiation” and “perpetuation” are widely used to interpret the activation process.27 Briefly, initiation is characterized by event that vitamin A-rich quiescent HSCs, stimulated by inflammatory factors, downregulate vitamin A, glial fibrillary acidic protein, and peroxisome proliferator-activated receptor (PPAR)-γ.28 Perpetuation refers to lately event that a continual increase in inflammatory factors, growth factors and cytokines, and surrounding profibrotic cells rapidly inducing HSCs to enter the activated state.29,30 The mechanistic link between loss of lipids in HSCs and cell activation is not well understood, but is thought to involve remarkable influence of the molecular and cellular pathways in hepatic inflammatory microenvironment.30–32 Cellular crosstalk between HSCs and surrounding multiple tissue-resident cells,33,34 including macrophages,35,36 neutrophils,37,38 platelets,33,39 dendritic cells,40 sinusoidal endothelial cells,41,42 epithelial cells,43 natural killer cells,44,45 various T lymphocytes,46,47 and B cells,48,49 promotes or inhibits the activation of HSCs. For example, inflammation induced by liver injury triggers the recruitment of macrophages to the liver, where they produce cytokines and chemokines, such as TGF-β, platelet-derived growth factor (PDGF), tumor necrosis factor-alpha (TNF-α), IL-1β, oncostatin M (OSM), chemokine ligand 3/5 (CCL3/5), directly inducing HSC activation, and subsequently forming a definitely complex activation network.50–53 The notch signaling pathway also transmits activation signals to HSCs through ligand receptor interaction and communication with neighboring cells to increase the degree of fibrosis.54 On one hand, Hedgehog signaling involves in the activation of HSCs by inducing transdifferentiation into MFBs responsible for matrix deposition.55,56 On the other hand, the Hedgehog pathway can inhibit apoptotic signals and enhance the viability and proliferation of MFBs, which leads to endogenous Hedgehog ligand generation in an autocrine or paracrine manner, followed by a positive feedback loop of Hedgehog signaling.55,57 Notably, some classical signaling pathways and emerging pathways synergistically promote HSC activation, hepatic fibrosis and even cross,58–60 like Hedgehog-Yes-associated protein (YAP), YAP-transcriptional coactivator with PDZ-binding motif (TAZ), YAP1-p38. The ECM, mainly composed of laminin, collagen, and proteoglycan, is required for HSC activation.61,62 After HSC activation, type IV collagen, heparan sulfate proteoglycan, and laminin are converted into type I and type III fibrous collagen by integrin, forming a positive feedback loop.63,64 During the transformation process, integrins bridge the connection between qHSCs and aHSCs.65,66 Type I collagen is one of the most abundant structural proteins in the fibrotic liver. It is regulated by RNA binding proteins at the post transcriptional level involved with mRNA processing, transport, stabilization, and translation.67,68 HSC activation is established as the main facilitator of liver fibrosis and carcinogenesis, but much remains to be clarified about its contribution to hepatic homeostasis, fibrosis resolution, and cancer initiation.

Activation of HSCs and pathophysiological role of HSC-derived exosomes.
Fig. 1  Activation of HSCs and pathophysiological role of HSC-derived exosomes.

Cellular crosstalk between HSCs and surrounding multiple tissue-resident cells promotes or inhibits the activation of HSCs. HSC-derived exosomes are involved in the occurrence and development of liver diseases through the regulation of retinoid metabolism, lipid metabolism, glucose metabolism, protein metabolism, and mitochondrial metabolism. HSC, hepatic stellate cell.

Pathophysiological role of HSC-derived exosomes

Retinoid metabolism

Of note, 50–95% of the body’s vitamin A, including retinol and its metabolites, is stored in HSCs and acts as an important regulator of retinoic acid homeostasis. Under physiological conditions, retinoids in HSCs are associated with several perilipins, which reduce HSC activation through increased expression. The mechanism is potentially involved in retinoid droplet stabilization and decreased catabolism.69 HSC activation and transdifferentiation into MFBs appears to require retinol release and loss of lipid droplets, which may be essential to fuel this metabolically required cellular response.70 Although the exact mechanistic relationship between exosomes and retinoid metabolism in HSCs has not been defined, partial answers have been revealed in several studies. In a mouse model of acute liver injury induced by CCl4, combining vitamin A with adipose mesenchymal stem cell (ASC)-derived exosomes promoted the liver targeting of exosomes, and vitamin A-loaded ASC exosomes reduced the rapid senescence-like response.71 We hypothesized that HSCs received vitamin A-loaded ASC exosomes to alleviate liver injury based on the characteristics of retinoid metabolism in HSCs. More relevant in-depth research needs to be performed. Moreover, autophagy plays a crucial role in the deprivation of retinyl ester-containing lipid droplets and adipogenic factors in HSCs by a selective autophagy process known as lipophagy, thus determining the activated phenotype of HSCs.72,73 Emerging evidence indicates reciprocal regulation of autophagy and exosome biogenesis by intertwined molecular machinery. Therefore, HSC-derived exosomes involved in retinoid metabolism are inhibited by autophagy that prevents the extracellular release of exosomes. Although the exact mechanistic relationship between exosomes and retinoid metabolism in HSCs has not yet been precisely examined, further investigation is necessary to gain insight into the complete mechanism.

Lipid metabolism

A growing number of studies have found that several LD-related proteins present during HSC activation regulate the activation of HSCs by regulating lipid metabolism, such as decreased expression of external perilipin 5 (Plin5)74 and liver fatty acid-binding protein (L-Fabp).75 Moreover, emerging evidence indicates that exosomes play a central role in lipid metabolism of HSCs through cell-to-cell communication. A study on lipogenic enzymes in HSCs found that cancer cell-derived exosomes have a significant and positive association with lipogenesis given that the levels of lipid contents, such as ATP citrate lyase (ACLY), fatty acid synthase (FASN) and ubiquitin-specific protease 2a (USP2a), were increased in exosome-challenged HSCs.76 In addition, HSPC111 was identified as a leading upregulated gene in HSCs incubated with colorectal cancer (CRC) cell-derived exosomes. HSPC111 altered the lipid metabolism of LX-2 by phosphorylating ACLY, revealing its promoting role in premetastatic niche formation and colorectal cancer liver metastases by reprogramming lipid metabolism in HSCs.77 Therefore, the available evidence suggests that exogenous exosomes greatly affect the activation of lipid metabolism in HSCs.

Glucose metabolism

Glucose metabolism plays an important role in the activation of HSCs, and aHSCs correspondingly upregulate glycolysis to meet the energy requirements for the phenotypic transformation of MFBs. Importantly, modulation of glucose metabolism is not only a marker of the MFB phenotype but also contributes to activation.1,78 aHSCs in primary culture significantly enhance glucose transportation and glycolysis activity.79 Intriguingly, glucose transporters, including pyruvate dehydrogenase kinase 3 (PDK3),79 glucose transporter (GLUT) 1,79 GLUT2,80 and GLUT481 are expressed in primary mouse HSCs and human LX-2 cells. High extracellular glucose or purinergic signaling conditions modulate the expression of these glucose transported. Hypoxia inducible factor-1 alpha (HIF-1α) signaling enhances exosome secretion from aHSCs and further stimulates HSC activation under hypoxic and inflammatory conditions.82 After information transfer via exosomes, even under the condition of sufficient oxygen, HSCs still preferentially perform glycolysis rather than oxidative phosphorylation to produce ATP, and this characteristic is called the Warburg effect. On the other hand, the increased glycolysis of cultured HSCs is accompanied by the diversion of central carbon metabolites from the citric acid cycle.83,84 Exosomes provide a mechanism for the rapid induction of glycolysis to support metabolic reprogramming from qHSCs to aHSCs to synchronize the stromal-cell injury response.

Protein metabolism

Our previous gene microarray analysis of tumor-activated HSCs showed a response to the stimulation of inflammation and tumors, and the considerable changes in genetic regulation and protein metabolism in aHSCs were associated with biological processes, molecular functions, and signaling pathways involved in the microenvironments of fibrogenesis, inflammation, and cancer.85 A comparative study of metabolic genes differentially expressed between qHSCs and aHSCs showed that only 6% of such genes were involved in carbohydrate metabolism, whereas 38% were involved in protein metabolism.59 Interestingly, the transformation of glutamine decomposition is particularly important in the process of protein metabolism. Recently, proteomic analysis of extracellular vesicles (EVs) from mouse HSCs found that the dynamic changes in the function and proteome composition of HSC-derived EVs during cell activation likely contributed to the regulation of HSC function and fine-tuning of fibrogenic pathways in the liver.86 In fact, exosomes have an important role in crosstalk between HSCs and hepatocytes, hepatic macrophages, or other types of cells, as they transfer their cargo, such as proteins and genes to recipient cells, and the exosomal miRNA profile is also altered.87 Numerous reports have demonstrated that HSC-derived exosomes actively participate in the pathological changes of various liver diseases, all of which are achieved by changes in the protein levels of key signaling pathway molecules.88–91

Mitochondrial metabolism

Compared to qHSCs with limited mitochondria, aHSCs have abundant mitochondria. During mitochondrial metabolism in aHSCs, the distinctive increase in mitochondrial membrane potential could sensitize the “bioenergetic signature” of fibrogenic HSCs for selective inhibition by mitotropic doxorubicin.92 To date, related research on the effects of exosomes from HSCs on mitochondrial metabolism is limited. However, several reports have provided evidence that paracrine exosomes, especially from hepatocytes, influence mitochondrial metabolism in HSCs through cell-to-cell communication in pathological conditions. Dong et al.93 noted that exosomes from hepatocytes (L-02 cells) treated with citreoviridin, a mycotoxin and ectopic ATP synthase inhibitor, induced mitochondrial calcium accumulation in aHSCs. In turn, pharmacological inhibition of mitochondrial calcium uptake alleviated the exosome-activated fibrogenic response in aHSCs, shedding light on a potential new mechanism underlying liver fibrosis. Another finding confirmed that liver injury (CCl4 or acetaminophen) resulted in mitochondrial dysfunction and the subsequent release of mitochondrial DNA from injured hepatocytes to normal hepatocytes and aHSCs through EVs, finally mediating fibrogenic responses in aHSCs.94 Notably, mesenchymal stem cell (MSC)-exosomes alleviated liver fibrosis by triggering HSC ferroptosis mechanistically by promoting ferroptosis-like cell death, mitochondrial dysfunction, and lipid peroxidation in aHSCs.95 In the future, the direct effect of HSC-derived exosomes on mitochondrial metabolism in HSCs should not be underestimated. The pathophysiological role of HSC-derived exosomes is summarized in Figure 1 and Table 1.

Table 1

Summary of the mechanisms of HSC-derived and HSC-associated exosomes in various liver diseases

DiseaseCellular origin of exosomesContentMechanismReference
NAFLDAdipocytesTGF-β pathwayAdipocyte-derived exosomes could cause dysregulation of the TGF-β pathway after integration into hepatocytes and HSCs in NAFLD97
Lipotoxic hepatocytesmiR-1297-PTEN/PI3K/AktmiR-1297 secreted from lipotoxic hepatocytes could promote the activation and proliferation of HSCs through PTEN/PI3K/Akt signaling pathway, accelerating the progress of MAFLD and fibrosis98
HepatocytesmiR-27aExosomal miR-27a overexpression could damage mitochondria in a-HSCs, and promote the production of ROS, and stimulate the activation and proliferation of HSC-derived fibroblasts, finally, lipotoxic fatty acids further aggravated this phenomenon20
Chronic viral hepatitisHSCsClassic fibrogenic signalα-SMA, collagen I, TGF-β and PDGF-B in HSCs were activated, and then the corresponding expression pattern in HSCs-derived exosomes was destined to change and facilitate viral transmission and hepatocyte damage106–109
HSCsTetraspanin CD63The exosome-associated tetraspanin CD63, including secretions from HSCs, contributes to the efficient assembly and release of HBV. The HBV particles from CD63-depleted cells markedly induce a loss of large hepatitis B surface antigens, then downregulate infectivity of the HBV101
HCV-infected hepatocytesmiR-19aExosomes from hepatocytes infected with HCV could regulate the SOCS-STAT3 axis and activate HSC via miR-19a102
HCV-infected hepatocytesmiR-192Exosomes derived from hepatocytes infected with HCV also transferred miR-192 to HSCs and then promoted fibrosis111
HBV-infected hepatocytesmiR-222Expression level of miR-222 was significantly increased in the exosomes from HBV infected hepatocytes, and significantly enhanced the activation of HSCs by inhibiting TFRC and TFRC induced ferroptosis112
Acute liver injuryHSCsHIF-PKM2/GLUT1HIF-1 in exosomes of HSCs inhibited the increased expression of PKM2 and GLUT1, and then, reduced hepatocyte damage in the glycolysis pathway116
HSCsn-APAP /H2O2HSC-MVs dose-dependently increased the viability of hepatocytes and increased expression levels of LDH, ALT, and AST, and suppressed the hepatocytes apoptosis induced by n-APAP or H2O2 and activated caspase-3 expression117
Damaged hepatocytesRORγt-IL-17AHepatocyte-derived exosome-affected HSCs inversely promoted γδT cells to produce IL-17A via increasing the expression of RORγt and combine with unknown self-TLR3 ligands118
ALDSerum/plasmamiR-122, miR-155miR-122 and miR-155 were predominantly associated with the exosome-rich fraction after liver damage and inflammation stimulation during the process of ALD121
HSCsmiR19b, miR92Expression levels of miR19b and miR92 in HSC-derived exosomes were increased after alcohol exposure123
HepatocytesHeparin/integrinHSCs received the delivery of exosomal RNA payload in donor hepatocytes via downstream of heparin- or integrin-dependent binding interactions123
Liver fibrosisHSCsCCN2HSC exosomal CCN2 in conjunction with other exosome constituents may amplify or fine tune fibrogenic signaling127
PMFsVEGF-VEGFR2PMFs release particles containing VEGF and activate VEGF receptor 2 in endothelial cells, thus greatly promoting angiogenesis128
HSCsIL-6,TNFαActivated human HSCs-exosomes stimulated macrophage IL-6 and TNFα synthesis and release and macrophage migration, in fibrosis90
HSCsPDGF-Hh ligandsPDGF-treated HSCs released exosomal Hh ligands and induced similar Hh-dependent changes in hepatic sinusoidal endothelial cells gene expression129
HSCsHNF4αHSC-derived exosomes together with activated HNF4α partially induced the transdifferentiation of HSCs to hepatocyte-like phenotype128
Stem cellsmiR-92a-3p, miR-302-3p, miR-146a-5p, SphK1Human iPSCs-derived exosomal miR-92a-3p and miR-302-3p, liver stem cell-derived EVs miR-146a-5p and SECs-derived exosomal SphK1 shuttled profibrotic transcripts into HSCs, and alleviated fibrotic phenotype of HSCs131–133
Liver cancerHSCsmiR-148a-3pActivated HSC exosome-depleted miR-148a-3p accelerated HCC progression through ITGA5/PI3K/Akt axis88
HSCsDHFRActivated HSC exosomal DHFR induced M1 macrophage polarization of M0 macrophage enhancement89

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALD, alcohol-related liver disease; α-SMA, alpha-smooth muscle actin; CCN2, connective tissue growth factor; DHFR, dihydrofolate reductase; GLUT1, glucose transporter-1; HSC, hepatic stellate cell; HIF-1, hypoxia inducible factor-1; HCV, hepatitis C virus; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HNF4α, hepatocyte nuclear factor 4 alpha; iPSC, induced pluripotent stem cells; ITGA5, integrin alpha 5; LDH, lactic dehydrogenase; MV, extracellular vesicles; MAFLD, metabolic associated fatty liver disease; n-APAP, n-acetyl-p-aminophenol; NAFLD, nonalcoholic fatty liver disease; PTEN, phosphatase and tensin homolog; PDGF-B, platelet-derived growth factor-B; PMF, portal vein myofibroblasts; PI3K, phosphatidylinositol 3-kinase; RORγt, retinoic acid receptor-related orphan receptor γt; ROS, reactive oxygen species; SOCS, suppressor of cytokine signaling; STAT3, signal transducer and activator of transcription 3; SEC, sinusoidal endothelial cells; SphK1, sphingosine kinase 1; TLR3, toll-like receptor 3; TGF-β, transforming growth factor beta; TFRC, transferrin receptor; TNFα, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor.

Roles of HSC-derived exosomes in liver diseases

Nonalcoholic fatty liver disease

Pathogenetic metabolic mechanisms, including hepatic glucose and lipid metabolism, macrophage dysfunction, bile acid toxicity, and HSC activation, are responsible for the development of nonalcoholic fatty liver disease (NAFLD).96 The presence of exosomes in hepatocytes, adipocytes, and HSCs in the hepatic environment accelerates the progression of NAFLD. To date, there is no direct research evidence of the role of HSC-derived exosomes in NAFLD; however, several studies indirectly reveal the functional characteristics of those exosomes. For example, adipocyte exosomes cause dysregulation of the TGF-β pathway after integration into hepatocytes and HSCs, offering insight into the possible pathogenesis of NAFLD.97 High levels of miR-1297 in exosomes derived from lipotoxic hepatocytes promote HSC activation and proliferation through the PTEN/PI3K/Akt signaling pathway, accelerating the progression of NAFLD and leading to fibrosis.98 In NAFLD patients and mouse models, exosomal miR-27a damage the mitochondria in aHSCs and stimulate the activation and proliferation of HSC-derived fibroblasts, which could be further aggravated by lipotoxic fatty acids.20 Whether NAFLD aggravation results from excess production and direction induction of exosomes in HSCs remains debated.

Chronic viral hepatitis

Exosomes contribute to the life cycle of hepatitis viruses, including replication, transition, and pathogenesis.99 Hepatitis viruses (HBV100,101 and HCV102,103) efficiently transfer bioactive components utilizing the exosome pathway from infected cells to naïve cells. Additionally, hepatitis B virus e antigen was demonstrated to induce the activation of HSCs.104,105 HSC activation is closely related to liver fibrosis in chronic hepatitis virus infection by some classic fibrogenic signals, such as α-SMA,106 collagen I,107 TGF-β,108 and platelet-derived growth factor-B (PDGF-B).109 Once those signaling molecules in HSCs are activated, the corresponding expression pattern in HSC-derived exosomes is destined to change, thereby enhancing the crosstalk between hepatocytes and the stromal environment, facilitating viral transmission and aggravating hepatocyte damage.110 The exosome-associated tetraspanin CD63, including secretions from HSCs, contributes to the efficient assembly and release of HBV. Ninomiya et al.101 found that the HBV particles from CD63-depleted cells markedly induce the loss of large hepatitis B surface antigens and downregulate infectivity of the HBV. Extracellular factors that interfere with HSCs, especially infected hepatocyte-derived exosomes, also have critical roles in chronic viral hepatitis-related liver diseases. Related studies have demonstrated that exosomes from viral hepatitis-replicating hepatocytes transfer various miRNAs (e.g., miR-19a,102 miR-192,111 and miR-222112) into HSCs to upregulate fibrogenic molecules, resulting in activation, and transdifferentiation into MBFs. A detailed understanding of the mechanisms associated with HSC-derived exosomes at the molecular level may contribute to the development of a new therapy direction to prevent hepatitis virus infection.

Acute liver injury

Considerable evidence has suggested that exosomes have important roles not only in the pathogenic progression of chronic liver disease but also in the initial onset of acute liver injury.113–115 HSC-derived exosomes are considered to be one of the most prominent indicators of the degree of liver damage,21 which is supported by a series of experimental studies. To date, most investigations of HSC-derived exosomes on liver damage have focused on chronic liver injury and persisting consequences that result in acute liver injury. Wan et al.116 provided clues regarding the involvement of HSCs in which inhibition of HIF-1 in exosomes released from HSCs suppressed the increased expression of pyruvate kinase M2 (PKM2) and GLUT1, markers of glycolysis, thus quickly reducing hepatocyte damage in the glycolysis pathway. Conversely, HSC-derived EVs protect hepatocytes from toxic-induced acute damage. Of note, HSC-MVs dose-dependently improved the viability of hepatocytes, inhibited hepatocyte apoptosis, increased the expression levels of lactate dehydrogenase, alanine aminotransaminase, and aspartate aminotransferase induced by n-acetyl-p-aminophenol n-(APAP) or H2O2, and activated caspase-3 expression.117 Following acute liver injury, damaged hepatocyte-derived exosome-treated HSCs inversely stimulated γδ T cells to produce IL17A by increasing the expression of RORγt and combining with unknown self-TLR3 ligands. The finding suggests a regulatory response of HSCs recruited from exosomes of hepatocytes containing unknown mediators, such as miRNAs, at early stages of liver injury.118 Therefore, with the exception of HSCs, exosomes from a variety of cell types participate in the process of acute liver injury through intercellular information transmission.

Alcoholic liver disease

Recent studies suggest that HSCs regulates parenchymal cell injury and inflammation that drive fibrogenesis in alcohol-related liver disease (ALD), but the mechanism remains incompletely defined.119,120 Accordingly, the pathophysiological role of exosomes associated with HSCs in ALD is increasingly recognized based on their properties of cell-to-cell communication. First, in ALD liver injury, serum/plasma miR-122 and miR-155 levels were predominantly associated with the exosome-rich fraction,121 and the number of exosomes was significantly increased in serum,122 indicating that microRNAs (miRNAs) and exosomes may be biomarkers of liver damage and inflammation during the process of ALD. Consistently, exposure to alcohol and its metabolites can enhance the expression of profibrotic markers in HSCs, concomitant with significantly increased miR19b and miR92 in HSC-derived exosomes.123 Furthermore, as a principal target of hepatocyte-derived exosomes, HSCs could receive the delivery of exosomal RNA payload in hepatocytes at intrinsic levels through the release of exosomes by donor hepatocytes, which occurs downstream of heparin- or integrin-dependent binding interactions.124 The studies provide insight into endogenous and exogenous exosomes in aHSCs as therapeutic targets for ALD liver injury.

Liver fibrosis

Liver fibrosis results from the dynamic net accumulation of ECM due to chronic liver injury based on the abovementioned etiology. The process mainly involves intercellular communication between HSCs and inflammation-damaged hepatocytes.29,125,126 In hepatic fibrosis, diverse intracellular signaling cascades maintain the activated phenotype and control the fibrogenic and proliferative state of HSCs. Exosomes represent an emerging means of intercellular signaling in the inflammation-irritated liver microenvironment undergoing coordinated immune responses to liver repair. HSC exosomal CCN2 in conjunction with other exosome constituents induces shifts between qHSCs or aHSCs and may amplify or fine tune fibrogenic signaling.127 In the study of hepatic fibrosis caused by portal vein dilation, portal vein myofibroblasts (PMFs), which are transdifferentiated from aHSCs, act the key cells of hepatic vascular remodeling. PMFs release microvesicles containing VEGF and activate VEGF receptor 2 in SECs, thus greatly promoting angiogenesis and providing a larger fibrotic skeleton for liver cirrhosis.128 Benbow et al.90 found that activated human HSC exosomes stimulated macrophage IL6 and TNF-α synthesis and release as well as macrophage migration, which was innately linked to the hepatic immune response to fibrosis. In addition, PDGF-treated HSCs released exosomes containing biologically active Hh ligands and induced similar Hh-dependent changes in hepatic sinusoidal endothelial cell (SEC) gene expression, suggesting a novel mechanism for vascular remodeling during cirrhosis.129 Based on the signal transduction and biological effects exerted by exosomes, mouse liver AML12 cell exosomes encapsulating the CRISPR/dCas9-VP64 system were delivered to HSCs. In turn, the engineered HSC-derived exosomes together with activated hepatocyte nuclear factor 4 alpha (HNF4α) partially induced the transdifferentiation of HSCs to a hepatocyte-like phenotype.130 Similarly, human induced pluripotent stem cell (iPSC)-derived exosomal miR-92a-3p and miR-302-3p,131 liver stem cell-derived EV miR-146a-5p,132 and SEC-derived exosomal SphK1133 shuttled profibrotic transcripts into HSCs and alleviated the fibrotic phenotype of HSCs. Together, the fibrogenesis mechanisms involved are not yet completely understood, but the findings suggest that imbalance of diverse extra- and intra-HSC-exosomal profibrotic or antifibrotic factors may determine the development of liver fibrosis.

Liver cancer

Chronic liver disease with fibroinflammation contributes not only to fibrosis but also hepatocyte regeneration as well as replication-induced DNA damage, all of which may promote the development of liver cancer.134–139 Extensive data have described exosomes as carriers of various cargoes conveying cellular information that enables them to serve as important players in malignant cell–nonmalignant cell communication during cancer developemnt.88,140–142 miRNA expression profiling of HSCs cocultured with liver cancer cells showed that miR-148a-3p was significantly reduced in HSCs.88 Subsequent studies demonstrated that aHSC exosome-depleted miR-148a-3p accelerated hepatocellular carcinoma (HCC) progression through the ITGA5/PI3K/Akt axis. To validate the effects of HSC-derived exosomes on effective intercellular transportation and information integration, Peng, et al.89 provided related evidence that aHSC exosomal DHFR induced M1 macrophage polarization of M0 macrophages. Two interesting studies verified that the exosomes secreted by qHSCs do not have the ability to affect liver cancer cells, whereas senescent HSC or aHSC exosomes promote the progression of HCC.143,144 In the tumor microenvironment, cancer cell-derived exosomes and HSC-derived exosomes mediate intercellular communication and form a positive feedback loop, thereby jointly constructing a prometastatic milieu suitable for the invasion and metastasis of tumor cells.145 After the education of pancreatic cancer cells74 or colorectal cancer cells77 by exosomes, aHSCs were identified as a component of the potential premetastatic niche that promotes liver metastasis. The detailed mechanisms of HSC-derived or HSC-associated exosomes in tumor invasion and metastasis remain incompletely characterized and more in-depth research work needs to be performed. The roles of HSC-derived exosomes in liver diseases are summarized in Figure 2.

Brief summary of the roles of HSC-derived exosomes in liver diseases and involved molecules and signaling pathways.
Fig. 2  Brief summary of the roles of HSC-derived exosomes in liver diseases and involved molecules and signaling pathways.

Various types of cells, such as hepatocytes, macrophages, adipocytes, and endothelial cells, exhibit intercellular communication with HSCs via extracellular vesicles (EVs) and significantly affect the processes associated with various liver diseases, such as acute liver injury, alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, fibrosis, and cancer, through the modulation of some critical molecules and signaling pathways. HSC, hepatic stellate cell. EVs, extracellular vesicles.

Clinical value of HSC-derived exosomes in liver diseases

Currently, early and accurate diagnostic, therapeutic and prognostic biomarkers of various liver diseases are lacking. Additionally, there are relatively few applied and translational studies of HSC-derived exosomes in liver diseases. Most relevant studies focus on exosomes derived from hepatocytes, nonparenchymal cells and nonparenchymal immune cells or exosomal mRNAs and ncRNAs, such as lncRNAs, miRNAs, and circRNAs. Recently, as potential biomarkers assessed by liquid biopsy, the safety and reliability of methods used to evaluate exosomes in patients and the therapeutic effect of exosomes have been evaluated in various liver diseases, such as ALD,146 NAFLD,147 viral hepatitis,148 fibrosis,149 and liver cancer.150

HSC-associated exosomes may offer potential clinical benefits for liver diseases, mainly fibrosis and cancer. In fibrosis, as mentioned above,116 HSC exosomal GLUT1 and PKM2 interfere with the metabolic activity of liver nonparenchymal cells around the liver through the glycolytic pathway, representing a new therapeutic target of liver fibrosis. Regarding extracellular exosomes targeted to HSCs, M2 macrophage-derived exosomal miR-411-5p inhibited HSC activation to inactivate stellate cells in an NAFLD model by directly downregulating the expression of calmodulin-regulated spectrin-associated protein 1 (CAMSAP1). Thus, an exosomal miR-411-5p inhibitor may serve as a potential therapeutic target for NAFLD and fibrosis.35 Similarly, through targeting HSCs, several exosomal microRNAs originating from other cell types, such as liver stem cells (miR-141-3p151 and miR-146a-5p132) and hepatocytes (miRNA-26b,152 miRNA-107,153 and miR-19a102) have biological effects that influence the fibrogenic phenotype of HSCs.

In the liver cancer microenvironment, on the one hand, HSC exosomal microRNAs and mRNAs (miR-148a-3p88 and DHFR89) participate in the malignant behavior of tumors via intercellular information shuttling. On the other hand, exosomes from liver cancer cells stimulate multiple signaling pathways (IGF2-PI3K.154 HSPC111-CXCL5-CXCR2,77 IL-6-STAT3,155 and MIRLET7BHG-miR-330-5p-SMO156 axes) in HSCs, subsequently contribute to tumor development and consequently provide potential targets for the prevention and treatment of liver cancer. The studies suggest that exosomal miRNAs and mRNAs derived from HSCs or targeted to HSCs are major regulators of tumor homeostasis and have bright prospects for clinical application.

Conclusions and perspectives

As multifaceted regulators in liver diseases responding to their activated state, HSCs generate corresponding cytokines and microRNAs that interact with adjacent cells during changes in glucose metabolism, lipid metabolism, amino acid metabolism, protein metabolism, and mitochondrial metabolism, in which HSC-derived exosomes have important roles. During the activation process, the metabolic regulation of HSC-derived exosomes may provide important information regarding the prevention and treatment of various liver diseases. An increasing number of studies highlight key extra- and intracellular exosomal pathways involved in HSC activation. In the near future, more in-depth research data are urgently needed to provide references for the potential translational and clinical application of exosomes derived from or associated with HSCs for various liver diseases.

Abbreviations

α-SMA: 

alpha-smooth muscle actin

aHSCs: 

activated hepatic stellate cells

ALD: 

alcohol-related liver disease

ASC: 

adipose mesenchymal stem cell

ECM: 

extracellular matrix

EVs: 

extracellular vesicles

GLUT: 

glucose transporter

HSCs: 

Hepatic stellate cells

IL: 

interleukin

MFBs: 

myofibroblasts

NAFLD: 

nonalcoholic fatty liver disease

PDGF: 

platelet-derived growth factor

qHSCs: 

quiescent hepatic stellate cells

TGF-β: 

transforming growth factor beta

TNF-α: 

tumor necrosis factor-alpha

VEGF: 

vascular endothelial growth factor

YAP: 

Yes-associated protein

Declarations

Funding

This study was supported by Japanese China Sasakawa Medical Fellowship, Science and Health Joint Research Project of Chongqing Municipality (2020GDRC013) and Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0087).

Conflict of interest

RL has been an editorial board member of Journal of Clinical and Translational Hepatology since 2021. The other authors have no conflicts of interest related to this publication.

Authors’ contributions

Study concept and design (KLY, ML, QG, RL), drafting of the manuscript (KLY, ML, YXD, WTY, QG, RL), critical revision of the manuscript for important intellectual content (KLY, ML, PPS, YXD, WTY, WT, NK, RL, QG). All authors have made a significant contribution to this study and have approved the final manuscript.

References

  1. Trivedi P, Wang S, Friedman SL. The Power of Plasticity-Metabolic Regulation of Hepatic Stellate Cells. Cell Metab 2021;33(2):242-257 View Article PubMed/NCBI
  2. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008;88(1):125-172 View Article PubMed/NCBI
  3. Bourebaba N, Marycz K. Hepatic stellate cells role in the course of metabolic disorders development - A molecular overview. Pharmacol Res 2021;170:105739 View Article PubMed/NCBI
  4. Wang S, Friedman SL. Hepatic fibrosis: A convergent response to liver injury that is reversible. J Hepatol 2020;73(1):210-211 View Article PubMed/NCBI
  5. Urushima H, Yuasa H, Matsubara T, Kuroda N, Hara Y, Inoue K, et al. Activation of Hepatic Stellate Cells Requires Dissociation of E-Cadherin-Containing Adherens Junctions with Hepatocytes. Am J Pathol 2021;191(3):438-453 View Article PubMed/NCBI
  6. Yu X, Elfimova N, Muller M, Bachurski D, Koitzsch U, Drebber U, et al. Autophagy-Related Activation of Hepatic Stellate Cells Reduces Cellular miR-29a by Promoting Its Vesicular Secretion. Cell Mol Gastroenterol Hepatol 2022;13(6):1701-1716 View Article PubMed/NCBI
  7. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science 2020;367(6478):eaau6977 View Article PubMed/NCBI
  8. Doyle LM, Wang MZ. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells 2019;8(7):727 View Article PubMed/NCBI
  9. Menu E, Vanderkerken K. Exosomes in Multiple Myeloma: from bench to bedside. Blood 2022:blood.2021014749 View Article PubMed/NCBI
  10. Dao TNT, Kim MG, Koo B, Liu H, Jang YO, Lee HJ, et al. Chimeric nanocomposites for the rapid and simple isolation of urinary extracellular vesicles. J Extracell Vesicles 2022;11(2):e12195 View Article PubMed/NCBI
  11. Zhang Y, Kim MS, Jia B, Yan J, Zuniga-Hertz JP, Han C, et al. Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature 2017;548(7665):52-57 View Article PubMed/NCBI
  12. Zheng X, Chen F, Zhang Q, Liu Y, You P, Sun S, et al. Salivary exosomal PSMA7: a promising biomarker of inflammatory bowel disease. Protein Cell 2017;8(9):686-695 View Article PubMed/NCBI
  13. Aarts J, Boleij A, Pieters BCH, Feitsma AL, van Neerven RJJ, Ten Klooster JP, et al. Flood Control: How Milk-Derived Extracellular Vesicles Can Help to Improve the Intestinal Barrier Function and Break the Gut-Joint Axis in Rheumatoid Arthritis. Front Immunol 2021;12:703277 View Article PubMed/NCBI
  14. Qiu M, Liu D, Fu Q. MiR-129-5p shuttled by human synovial mesenchymal stem cell-derived exosomes relieves IL-1beta induced osteoarthritis via targeting HMGB1. Life Sci 2021;269:118987 View Article PubMed/NCBI
  15. Babajani A, Moeinabadi-Bidgoli K, Niknejad F, Rismanchi H, Shafiee S, Shariatzadeh S, et al. Human placenta-derived amniotic epithelial cells as a new therapeutic hope for COVID-19-associated acute respiratory distress syndrome (ARDS) and systemic inflammation. Stem Cell Res Ther 2022;13(1):126 View Article PubMed/NCBI
  16. Su Q, Zhang Y, Cui Z, Chang S, Zhao P. Semen-Derived Exosomes Mediate Immune Escape and Transmission of Reticuloendotheliosis Virus. Front Immunol 2021;12:735280 View Article PubMed/NCBI
  17. Wang Y, Liu J, Ma J, Sun T, Zhou Q, Wang W, et al. Exosomal circRNAs: biogenesis, effect and application in human diseases. Mol Cancer 2019;18(1):116 View Article PubMed/NCBI
  18. Pegtel DM, Gould SJ. Exosomes. Annu Rev Biochem 2019;88:487-514 View Article PubMed/NCBI
  19. Luan SH, Yang YQ, Ye MP, Liu H, Rao QF, Kong JL, et al. ASIC1a promotes hepatic stellate cell activation through the exosomal miR-301a-3p/BTG1 pathway. Int J Biol Macromol 2022;211:128-139 View Article PubMed/NCBI
  20. Luo X, Xu ZX, Wu JC, Luo SZ, Xu MY. Hepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD. Mol Ther Nucleic Acids 2021;26:1241-1254 View Article PubMed/NCBI
  21. Sung S, Kim J, Jung Y. Liver-Derived Exosomes and Their Implications in Liver Pathobiology. Int J Mol Sci 2018;19(12):3715 View Article PubMed/NCBI
  22. Chen L, Chen R, Kemper S, Charrier A, Brigstock DR. Suppression of fibrogenic signaling in hepatic stellate cells by Twist1-dependent microRNA-214 expression: Role of exosomes in horizontal transfer of Twist1. Am J Physiol Gastrointest Liver Physiol 2015;309(6):G491-499 View Article PubMed/NCBI
  23. Chen L, Brigstock DR. Integrins and heparan sulfate proteoglycans on hepatic stellate cells (HSC) are novel receptors for HSC-derived exosomes. FEBS Lett 2016;590(23):4263-4274 View Article PubMed/NCBI
  24. Atzori L, Poli G, Perra A. Hepatic stellate cell: a star cell in the liver. Int J Biochem Cell Biol 2009;41(8-9):1639-1642 View Article PubMed/NCBI
  25. Vallverdu J, Martinez Garcia de la Torre RA, Mannaerts I, Verhulst S, Smout A, Coll M, et al. Directed differentiation of human induced pluripotent stem cells to hepatic stellate cells. Nat Protoc 2021;16(5):2542-2563 View Article PubMed/NCBI
  26. Midorikawa Y, Takayama T, Higaki T, Aramaki O, Teramoto K, Yoshida N, et al. High platelet count as a poor prognostic factor for liver cancer patients without cirrhosis. Biosci Trends 2020;14(5):368-375 View Article PubMed/NCBI
  27. Barcena-Varela M, Colyn L, Fernandez-Barrena MG. Epigenetic Mechanisms in Hepatic Stellate Cell Activation During Liver Fibrosis and Carcinogenesis. Int J Mol Sci 2019;20(10):2507 View Article PubMed/NCBI
  28. Kamm DR, McCommis KS. Hepatic stellate cells in physiology and pathology. J Physiol 2022;600(8):1825-1837 View Article PubMed/NCBI
  29. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 2017;14(7):397-411 View Article PubMed/NCBI
  30. Yan Y, Zeng J, Xing L, Li C. Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation. Biomedicines 2021;9(8):1014 View Article PubMed/NCBI
  31. Beringer A, Miossec P. IL-17 and TNF-alpha co-operation contributes to the proinflammatory response of hepatic stellate cells. Clin Exp Immunol 2019;198(1):111-120 View Article PubMed/NCBI
  32. Widjaja AA, Singh BK, Adami E, Viswanathan S, Dong J, D’Agostino GA, et al. Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Nonalcoholic Steatohepatitis. Gastroenterology 2019;157(3):777-792.e714 View Article PubMed/NCBI
  33. Yang F, Li H, Li Y, Hao Y, Wang C, Jia P, et al. Crosstalk between hepatic stellate cells and surrounding cells in hepatic fibrosis. Int Immunopharmacol 2021;99:108051 View Article PubMed/NCBI
  34. Zhou BY, Gong JH, Cai XY, Wang JX, Luo F, Jiang N, et al. An imbalance between stellate cells and gammadeltaT cells contributes to hepatocellular carcinoma aggressiveness and recurrence. Hepatol Int 2019;13(5):631-640 View Article PubMed/NCBI
  35. Wan Z, Yang X, Liu X, Sun Y, Yu P, Xu F, et al. M2 macrophage-derived exosomal microRNA-411-5p impedes the activation of hepatic stellate cells by targeting CAMSAP1 in NASH model. iScience 2022;25(7):104597 View Article PubMed/NCBI
  36. Shu B, Zhang RZ, Zhou YX, He C, Yang X. METTL3-mediated macrophage exosomal NEAT1 contributes to hepatic fibrosis progression through Sp1/TGF-beta1/Smad signaling pathway. Cell Death Discov 2022;8(1):266 View Article PubMed/NCBI
  37. Yang Q, Yan C, Gong Z. Interaction of hepatic stellate cells with neutrophils and macrophages in the liver following oncogenic kras activation in transgenic zebrafish. Sci Rep 2018;8(1):8495 View Article PubMed/NCBI
  38. Zhou Z, Xu MJ, Cai Y, Wang W, Jiang JX, Varga ZV, et al. Neutrophil-Hepatic Stellate Cell Interactions Promote Fibrosis in Experimental Steatohepatitis. Cell Mol Gastroenterol Hepatol 2018;5(3):399-413 View Article PubMed/NCBI
  39. Meyer J, Balaphas A, Fontana P, Morel P, Robson SC, Sadoul K, et al. Platelet Interactions with Liver Sinusoidal Endothelial Cells and Hepatic Stellate Cells Lead to Hepatocyte Proliferation. Cells 2020;9(5):1243 View Article PubMed/NCBI
  40. Xia YH, Lu Z, Wang SM, Hu LX. Nrf2 activation mediates tumor-specific hepatic stellate cells-induced DIgR2 expression in dendritic cells. Aging (Albany NY) 2019;11(23):11565-11575 View Article PubMed/NCBI
  41. Wu X, Shu L, Zhang Z, Li J, Zong J, Cheong LY, et al. Adipocyte Fatty Acid Binding Protein Promotes the Onset and Progression of Liver Fibrosis via Mediating the Crosstalk between Liver Sinusoidal Endothelial Cells and Hepatic Stellate Cells. Adv Sci (Weinh) 2021;8(11):e2003721 View Article PubMed/NCBI
  42. Hammoutene A, Rautou PE. Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease. J Hepatol 2019;70(6):1278-1291 View Article PubMed/NCBI
  43. Liu R, Li X, Zhu W, Wang Y, Zhao D, Wang X, et al. Cholangiocyte-Derived Exosomal Long Noncoding RNA H19 Promotes Hepatic Stellate Cell Activation and Cholestatic Liver Fibrosis. Hepatology 2019;70(4):1317-1335 View Article PubMed/NCBI
  44. Gao B, Radaeva S. Natural killer and natural killer T cells in liver fibrosis. Biochim Biophys Acta 2013;1832(7):1061-1069 View Article PubMed/NCBI
  45. Wang L, Wang Y, Quan J. Exosomes derived from natural killer cells inhibit hepatic stellate cell activation and liver fibrosis. Hum Cell 2020;33(3):582-589 View Article PubMed/NCBI
  46. Yang Y, Sheng Y, Wang J, Zhou X, Li W, Zhang C, et al. Double-Negative T Cells Regulate Hepatic Stellate Cell Activation to Promote Liver Fibrosis Progression via NLRP3. Front Immunol 2022;13:857116 View Article PubMed/NCBI
  47. Sun XF, Gu L, Deng WS, Xu Q. Impaired balance of T helper 17/T regulatory cells in carbon tetrachloride-induced liver fibrosis in mice. World J Gastroenterol 2014;20(8):2062-2070 View Article PubMed/NCBI
  48. Thapa M, Chinnadurai R, Velazquez VM, Tedesco D, Elrod E, Han JH, et al. Liver fibrosis occurs through dysregulation of MyD88-dependent innate B-cell activity. Hepatology 2015;61(6):2067-2079 View Article PubMed/NCBI
  49. Faggioli F, Palagano E, Di Tommaso L, Donadon M, Marrella V, Recordati C, et al. B lymphocytes limit senescence-driven fibrosis resolution and favor hepatocarcinogenesis in mouse liver injury. Hepatology 2018;67(5):1970-1985 View Article PubMed/NCBI
  50. Mack M. Inflammation and fibrosis. Matrix Biol 2018;68-69:106-121 View Article PubMed/NCBI
  51. Najar M, Fayyad-Kazan H, Faour WH, El Taghdouini A, Raicevic G, Najimi M, et al. Human hepatic stellate cells and inflammation: A regulated cytokine network balance. Cytokine 2017;90:130-134 View Article PubMed/NCBI
  52. Gupta G, Khadem F, Uzonna JE. Role of hepatic stellate cell (HSC)-derived cytokines in hepatic inflammation and immunity. Cytokine 2019;124:154542 View Article PubMed/NCBI
  53. Matsuda M, Seki E. Hepatic Stellate Cell-Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis. Semin Liver Dis 2020;40(3):307-320 View Article PubMed/NCBI
  54. Duan JL, Ruan B, Yan XC, Liang L, Song P, Yang ZY, et al. Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice. Hepatology 2018;68(2):677-690 View Article PubMed/NCBI
  55. Gao L, Zhang Z, Zhang P, Yu M, Yang T. Role of canonical Hedgehog signaling pathway in liver. Int J Biol Sci 2018;14(12):1636-1644 View Article PubMed/NCBI
  56. Yan J, Huang H, Liu Z, Shen J, Ni J, Han J, et al. Hedgehog signaling pathway regulates hexavalent chromium-induced liver fibrosis by activation of hepatic stellate cells. Toxicol Lett 2020;320:1-8 View Article PubMed/NCBI
  57. Lin X, Li J, Xing YQ. Geniposide, a sonic hedgehog signaling inhibitor, inhibits the activation of hepatic stellate cell. Int Immunopharmacol 2019;72:330-338 View Article PubMed/NCBI
  58. Wilhelm A, Aldridge V, Haldar D, Naylor AJ, Weston CJ, Hedegaard D, et al. CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism. Gut 2016;65(7):1175-1185 View Article PubMed/NCBI
  59. Du K, Hyun J, Premont RT, Choi SS, Michelotti GA, Swiderska-Syn M, et al. Hedgehog-YAP Signaling Pathway Regulates Glutaminolysis to Control Activation of Hepatic Stellate Cells. Gastroenterology 2018;154(5):1465-1479.e1413 View Article PubMed/NCBI
  60. Mooring M, Fowl BH, Lum SZC, Liu Y, Yao K, Softic S, et al. Hepatocyte Stress Increases Expression of Yes-Associated Protein and Transcriptional Coactivator With PDZ-Binding Motif in Hepatocytes to Promote Parenchymal Inflammation and Fibrosis. Hepatology 2020;71(5):1813-1830 View Article PubMed/NCBI
  61. Mohammadi M, Olsen SK, Goetz R. A protein canyon in the FGF-FGF receptor dimer selects from an a la carte menu of heparan sulfate motifs. Curr Opin Struct Biol 2005;15(5):506-516 View Article PubMed/NCBI
  62. Shi Y, Massagué J. Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus. Cell 2003;113(6):685-700 View Article PubMed/NCBI
  63. Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev 2017;121:27-42 View Article PubMed/NCBI
  64. Kanta J. Collagen matrix as a tool in studying fibroblastic cell behavior. Cell Adh Migr 2015;9(4):308-316 View Article PubMed/NCBI
  65. Nishimichi N, Tsujino K, Kanno K, Sentani K, Kobayashi T, Chayama K, et al. Induced hepatic stellate cell integrin, alpha8beta1, enhances cellular contractility and TGFbeta activity in liver fibrosis. J Pathol 2021;253(4):366-373 View Article PubMed/NCBI
  66. Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, et al. Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 2013;19(12):1617-1624 View Article PubMed/NCBI
  67. Hrckova G, Velebny S, Solar P. Dynamics of hepatic stellate cells, collagen types I and III synthesis and gene expression of selected cytokines during hepatic fibrogenesis following Mesocestoides vogae (Cestoda) infection in mice. Int J Parasitol 2010;40(2):163-174 View Article PubMed/NCBI
  68. Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol 2021;18(3):151-166 View Article PubMed/NCBI
  69. Zhou J, Cui S, He Q, Guo Y, Pan X, Zhang P, et al. SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis. Nat Commun 2020;11(1):240 View Article PubMed/NCBI
  70. Hernandez-Gea V, Friedman SL. Autophagy fuels tissue fibrogenesis. Autophagy 2012;8(5):849-850 View Article PubMed/NCBI
  71. Fang J, Liang W. ASCs -derived exosomes loaded with vitamin A and quercetin inhibit rapid senescence-like response after acute liver injury. Biochem Biophys Res Commun 2021;572:125-130 View Article PubMed/NCBI
  72. Lucantoni F, Martinez-Cerezuela A, Gruevska A, Moragrega AB, Victor VM, Esplugues JV, et al. Understanding the implication of autophagy in the activation of hepatic stellate cells in liver fibrosis: are we there yet?. J Pathol 2021;254(3):216-228 View Article PubMed/NCBI
  73. Filali-Mouncef Y, Hunter C, Roccio F, Zagkou S, Dupont N, Primard C, et al. The menage a trois of autophagy, lipid droplets and liver disease. Autophagy 2022;18(1):50-72 View Article PubMed/NCBI
  74. Barrera LN, Ridley PM, Bermejo-Rodriguez C, Costello E, Perez-Mancera PA. The role of microRNAs in the modulation of cancer-associated fibroblasts activity during pancreatic cancer pathogenesis. J Physiol Biochem 2022 View Article PubMed/NCBI
  75. Chen A, Tang Y, Davis V, Hsu FF, Kennedy SM, Song H, et al. Liver fatty acid binding protein (L-Fabp) modulates murine stellate cell activation and diet-induced nonalcoholic fatty liver disease. Hepatology 2013;57(6):2202-2212 View Article PubMed/NCBI
  76. Zhou Y, Ren H, Dai B, Li J, Shang L, Huang J, et al. Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts. J Exp Clin Cancer Res 2018;37(1):324 View Article PubMed/NCBI
  77. Zhang C, Wang XY, Zhang P, He TC, Han JH, Zhang R, et al. Cancer-derived exosomal HSPC111 promotes colorectal cancer liver metastasis by reprogramming lipid metabolism in cancer-associated fibroblasts. Cell Death Dis 2022;13(1):57 View Article PubMed/NCBI
  78. Xie D, Zhao X, Chen M. Prevention and treatment strategies for type 2 diabetes based on regulating intestinal flora. Biosci Trends 2021;15(5):313-320 View Article PubMed/NCBI
  79. Chen Y, Choi SS, Michelotti GA, Chan IS, Swiderska-Syn M, Karaca GF, et al. Hedgehog controls hepatic stellate cell fate by regulating metabolism. Gastroenterology 2012;143(5):1319-1329.e1311 View Article PubMed/NCBI
  80. Lin J, Chen A. Curcumin diminishes the impacts of hyperglycemia on the activation of hepatic stellate cells by suppressing membrane translocation and gene expression of glucose transporter-2. Mol Cell Endocrinol 2011;333(2):160-171 View Article PubMed/NCBI
  81. Chandrashekaran V, Das S, Seth RK, Dattaroy D, Alhasson F, Michelotti G, et al. Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis. Biochim Biophys Acta 2016;1862(1):32-45 View Article PubMed/NCBI
  82. Wang Y, Huang Y, Guan F, Xiao Y, Deng J, Chen H, et al. Hypoxia-inducible factor-1alpha and MAPK co-regulate activation of hepatic stellate cells upon hypoxia stimulation. PLoS One 2013;8(9):e74051 View Article PubMed/NCBI
  83. Icard P, Shulman S, Farhat D, Steyaert JM, Alifano M, Lincet H. How the Warburg effect supports aggressiveness and drug resistance of cancer cells?. Drug Resist Updat 2018;38:1-11 View Article PubMed/NCBI
  84. Liberti MV, Locasale JW. The Warburg Effect: How Does it Benefit Cancer Cells?. Trends Biochem Sci 2016;41(3):211-218 View Article PubMed/NCBI
  85. Liao R, Wu H, Yi Y, Wang JX, Cai XY, He HW, et al. Clinical significance and gene expression study of human hepatic stellate cells in HBV related-hepatocellular carcinoma. J Exp Clin Cancer Res 2013;32:22 View Article PubMed/NCBI
  86. Li X, Chen R, Kemper S, Brigstock DR. Dynamic Changes in Function and Proteomic Composition of Extracellular Vesicles from Hepatic Stellate Cells during Cellular Activation. Cells 2020;9(2):290 View Article PubMed/NCBI
  87. Hwang S, Yang YM. Exosomal microRNAs as diagnostic and therapeutic biomarkers in non-malignant liver diseases. Arch Pharm Res 2021;44(6):574-587 View Article PubMed/NCBI
  88. Zhang X, Chen F, Huang P, Wang X, Zhou K, Zhou C, et al. Exosome-depleted MiR-148a-3p derived from Hepatic Stellate Cells Promotes Tumor Progression via ITGA5/PI3K/Akt Axis in Hepatocellular Carcinoma. Int J Biol Sci 2022;18(6):2249-2260 View Article PubMed/NCBI
  89. Peng Y, Li Z, Chen S, Zhou J. DHFR silence alleviated the development of liver fibrosis by affecting the crosstalk between hepatic stellate cells and macrophages. J Cell Mol Med 2021;25(21):10049-10060 View Article PubMed/NCBI
  90. Benbow JH, Marrero E, McGee RM, Brandon-Warner E, Attal N, Feilen NA, et al. Hepatic stellate cell-derived exosomes modulate macrophage inflammatory response. Exp Cell Res 2021;405(1):112663 View Article PubMed/NCBI
  91. Mastoridou EM, Goussia AC, Glantzounis GK, Kanavaros P, Charchanti AV. Autophagy and Exosomes: Cross-Regulated Pathways Playing Major Roles in Hepatic Stellate Cells Activation and Liver Fibrosis. Front Physiol 2021;12:801340 View Article PubMed/NCBI
  92. Gajendiran P, Vega LI, Itoh K, Sesaki H, Vakili MR, Lavasanifar A, et al. Elevated mitochondrial activity distinguishes fibrogenic hepatic stellate cells and sensitizes for selective inhibition by mitotropic doxorubicin. J Cell Mol Med 2018;22(4):2210-2219 View Article PubMed/NCBI
  93. Dong Z, Yang X, Qiu T, An Y, Zhang G, Li Q, et al. Exosomal miR-181a-2-3p derived from citreoviridin-treated hepatocytes activates hepatic stellate cells trough inducing mitochondrial calcium overload. Chem Biol Interact 2022;358:109899 View Article PubMed/NCBI
  94. Li YJ, Liu RP, Ding MN, Zheng Q, Wu JZ, Xue XY, et al. Tetramethylpyrazine prevents liver fibrotic injury in mice by targeting hepatocyte-derived and mitochondrial DNA-enriched extracellular vesicles. Acta Pharmacol Sin 2022;43(8):2026-2041 View Article PubMed/NCBI
  95. Tan Y, Huang Y, Mei R, Mao F, Yang D, Liu J, et al. HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis. Cell Death Dis 2022;13(4):319 View Article PubMed/NCBI
  96. Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 2021;184(10):2537-2564 View Article PubMed/NCBI
  97. Koeck ES, Iordanskaia T, Sevilla S, Ferrante SC, Hubal MJ, Freishtat RJ, et al. Adipocyte exosomes induce transforming growth factor beta pathway dysregulation in hepatocytes: a novel paradigm for obesity-related liver disease. J Surg Res 2014;192(2):268-275 View Article PubMed/NCBI
  98. Luo X, Luo SZ, Xu ZX, Zhou C, Li ZH, Zhou XY, et al. Lipotoxic hepatocyte-derived exosomal miR-1297 promotes hepatic stellate cell activation through the PTEN signaling pathway in metabolic-associated fatty liver disease. World J Gastroenterol 2021;27(14):1419-1434 View Article PubMed/NCBI
  99. Shi Y, Du L, Lv D, Li Y, Zhang Z, Huang X, et al. Emerging role and therapeutic application of exosome in hepatitis virus infection and associated diseases. J Gastroenterol 2021;56(4):336-349 View Article PubMed/NCBI
  100. Hu Q, Wang Q, Zhang Y, Tao S, Zhang X, Liu X, et al. Baseline serum exosome-derived miRNAs predict HBeAg seroconversion in chronic hepatitis B patients treated with peginterferon. J Med Virol 2021;93(8):4939-4948 View Article PubMed/NCBI
  101. Ninomiya M, Inoue J, Krueger EW, Chen J, Cao H, Masamune A, et al. The Exosome-Associated Tetraspanin CD63 Contributes to the Efficient Assembly and Infectivity of the Hepatitis B Virus. Hepatol Commun 2021;5(7):1238-1251 View Article PubMed/NCBI
  102. Devhare PB, Sasaki R, Shrivastava S, Di Bisceglie AM, Ray R, Ray RB. Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells. J Virol 2017;91(6):e02225-16 View Article PubMed/NCBI
  103. Kim OK, Nam DE, Hahn YS. The Pannexin 1/Purinergic Receptor P2X4 Pathway Controls the Secretion of MicroRNA-Containing Exosomes by HCV-Infected Hepatocytes. Hepatology 2021;74(6):3409-3426 View Article PubMed/NCBI
  104. Zan Y, Zhang Y, Tien P. Hepatitis B virus e antigen induces activation of rat hepatic stellate cells. Biochem Biophys Res Commun 2013;435(3):391-396 View Article PubMed/NCBI
  105. Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 2010;7(8):425-436 View Article PubMed/NCBI
  106. Sun LJ, Yu JW, Shi YG, Zhang XY, Shu MN, Chen MY. Hepatitis C virus core protein induces dysfunction of liver sinusoidal endothelial cell by down-regulation of silent information regulator 1. J Med Virol 2018;90(5):926-935 View Article PubMed/NCBI
  107. Hamada-Tsutsumi S, Onishi M, Matsuura K, Isogawa M, Kawashima K, Sato Y, et al. Inhibitory Effect of a Human MicroRNA, miR-6133-5p, on the Fibrotic Activity of Hepatic Stellate Cells in Culture. Int J Mol Sci 2020;21(19):7251 View Article PubMed/NCBI
  108. Saha B, Kodys K, Szabo G. Hepatitis C Virus-Induced Monocyte Differentiation Into Polarized M2 Macrophages Promotes Stellate Cell Activation via TGF-beta. Cell Mol Gastroenterol Hepatol 2016;2(3):302-316.308 View Article PubMed/NCBI
  109. Bai Q, An J, Wu X, You H, Ma H, Liu T, et al. HBV promotes the proliferation of hepatic stellate cells via the PDGF-B/PDGFR-beta signaling pathway in vitro. Int J Mol Med 2012;30(6):1443-1450 View Article PubMed/NCBI
  110. Kapoor NR, Chadha R, Kumar S, Choedon T, Reddy VS, Kumar V. The HBx gene of hepatitis B virus can influence hepatic microenvironment via exosomes by transferring its mRNA and protein. Virus Res 2017;240:166-174 View Article PubMed/NCBI
  111. Kim JH, Lee CH, Lee SW. Exosomal Transmission of MicroRNA from HCV Replicating Cells Stimulates Transdifferentiation in Hepatic Stellate Cells. Mol Ther Nucleic Acids 2019;14:483-497 View Article PubMed/NCBI
  112. Zhang Q, Qu Y, Zhang Q, Li F, Li B, Li Z, et al. Exosomes derived from hepatitis B virus-infected hepatocytes promote liver fibrosis via miR-222/TFRC axis. Cell Biol Toxicol 2022 View Article PubMed/NCBI
  113. Lin F, Chen W, Zhou J, Zhu J, Yao Q, Feng B, et al. Mesenchymal stem cells protect against ferroptosis via exosome-mediated stabilization of SLC7A11 in acute liver injury. Cell Death Dis 2022;13(3):271 View Article PubMed/NCBI
  114. Jiao Y, Xu P, Shi H, Chen D, Shi H. Advances on liver cell-derived exosomes in liver diseases. J Cell Mol Med 2021;25(1):15-26 View Article PubMed/NCBI
  115. Devaraj E, Perumal E, Subramaniyan R, Mustapha N. Liver fibrosis: Extracellular vesicles mediated intercellular communication in perisinusoidal space. Hepatology 2022;76(1):275-285 View Article PubMed/NCBI
  116. Wan L, Xia T, Du Y, Liu J, Xie Y, Zhang Y, et al. Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells. FASEB J 2019;33(7):8530-8542 View Article PubMed/NCBI
  117. Huang R, Pan Q, Ma X, Wang Y, Liang Y, Dai B, et al. Hepatic Stellate Cell-Derived Microvesicles Prevent Hepatocytes from Injury Induced by APAP/H2O2. Stem Cells Int 2016;2016:8357567 View Article PubMed/NCBI
  118. Seo W, Eun HS, Kim SY, Yi HS, Lee YS, Park SH, et al. Exosome-mediated activation of toll-like receptor 3 in stellate cells stimulates interleukin-17 production by gammadelta T cells in liver fibrosis. Hepatology 2016;64(2):616-631 View Article PubMed/NCBI
  119. Arab JP, Cabrera D, Sehrawat TS, Jalan-Sakrikar N, Verma VK, Simonetto D, et al. Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12. J Hepatol 2020;73(1):149-160 View Article PubMed/NCBI
  120. Choi WM, Kim HH, Kim MH, Cinar R, Yi HS, Eun HS, et al. Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis. Cell Metab 2019;30(5):877-889.877 View Article PubMed/NCBI
  121. Bala S, Petrasek J, Mundkur S, Catalano D, Levin I, Ward J, et al. Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases. Hepatology 2012;56(5):1946-1957 View Article PubMed/NCBI
  122. Momen-Heravi F, Bala S, Kodys K, Szabo G. Exosomes derived from alcohol-treated hepatocytes horizontally transfer liver specific miRNA-122 and sensitize monocytes to LPS. Sci Rep 2015;5:9991 View Article PubMed/NCBI
  123. Brandon-Warner E, Feilen NA, Culberson CR, Field CO, deLemos AS, Russo MW, et al. Processing of miR17-92 Cluster in Hepatic Stellate Cells Promotes Hepatic Fibrogenesis During Alcohol-Induced Injury. Alcohol Clin Exp Res 2016;40(7):1430-1442 View Article PubMed/NCBI
  124. Chen L, Chen R, Kemper S, Brigstock DR. Pathways of production and delivery of hepatocyte exosomes. J Cell Commun Signal 2018;12(1):343-357 View Article PubMed/NCBI
  125. Chen P, Liu Y, Ma X, Li Q, Zhang Y, Xiong Q, et al. Replication Factor C4 in human hepatocellular carcinoma: A potent prognostic factor associated with cell proliferation. Biosci Trends 2021;15(4):249-256 View Article PubMed/NCBI
  126. Liao R, Fu YP, Wang T, Deng ZG, Li DW, Fan J, et al. Metavir and FIB-4 scores are associated with patient prognosis after curative hepatectomy in hepatitis B virus-related hepatocellular carcinoma: a retrospective cohort study at two centers in China. Oncotarget 2017;8(1):1774-1787 View Article PubMed/NCBI
  127. Charrier A, Chen R, Chen L, Kemper S, Hattori T, Takigawa M, et al. Exosomes mediate intercellular transfer of pro-fibrogenic connective tissue growth factor (CCN2) between hepatic stellate cells, the principal fibrotic cells in the liver. Surgery 2014;156(3):548-555 View Article PubMed/NCBI
  128. Lemoinne S, Cadoret A, Rautou PE, El Mourabit H, Ratziu V, Corpechot C, et al. Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles. Hepatology 2015;61(3):1041-1055 View Article PubMed/NCBI
  129. Witek RP, Yang L, Liu R, Jung Y, Omenetti A, Syn WK, et al. Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells. Gastroenterology 2009;136(1):320-330.322 View Article PubMed/NCBI
  130. Luo N, Li J, Chen Y, Xu Y, Wei Y, Lu J, et al. Hepatic stellate cell reprogramming via exosome-mediated CRISPR/dCas9-VP64 delivery. Drug Deliv 2021;28(1):10-18 View Article PubMed/NCBI
  131. Povero D, Pinatel EM, Leszczynska A, Goyal NP, Nishio T, Kim J, et al. Human induced pluripotent stem cell-derived extracellular vesicles reduce hepatic stellate cell activation and liver fibrosis. JCI Insight 2019;5(14):e125652 View Article PubMed/NCBI
  132. Chiabotto G, Ceccotti E, Tapparo M, Camussi G, Bruno S. Human Liver Stem Cell-Derived Extracellular Vesicles Target Hepatic Stellate Cells and Attenuate Their Pro-fibrotic Phenotype. Front Cell Dev Biol 2021;9:777462 View Article PubMed/NCBI
  133. Ye Q, Zhou Y, Zhao C, Xu L, Ping J. Salidroside Inhibits CCl4-Induced Liver Fibrosis in Mice by Reducing Activation and Migration of HSC Induced by Liver Sinusoidal Endothelial Cell-Derived Exosomal SphK1. Front Pharmacol 2021;12:677810 View Article PubMed/NCBI
  134. Maki H, Hasegawa K. Advances in the surgical treatment of liver cancer. Biosci Trends 2022;16(3):178-188 View Article PubMed/NCBI
  135. Schwabe RF, Luedde T. Apoptosis and necroptosis in the liver: a matter of life and death. Nat Rev Gastroenterol Hepatol 2018;15(12):738-752 View Article PubMed/NCBI
  136. Finn RS, Ikeda M, Zhu AX, Sung MW, Baron AD, Kudo M, et al. Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. J Clin Oncol 2020;38(26):2960-2970 View Article PubMed/NCBI
  137. Setoyama H, Tanaka Y, Kanto T. Seamless support from screening to anti-HCV treatment and HCC/decompensated cirrhosis: Subsidy programs for HCV elimination. Glob Health Med 2021;3(5):335-342 View Article PubMed/NCBI
  138. Yamazoe T, Mori T, Yoshio S, Kanto T. Hepatocyte ploidy and pathological mutations in hepatocellular carcinoma: impact on oncogenesis and therapeutics. Glob Health Med 2020;2(5):273-281 View Article PubMed/NCBI
  139. Liao R, Du CY, Gong JP, Luo F. HBV-DNA Load-Related Peritumoral Inflammation and ALBI Scores Predict HBV Associated Hepatocellular Carcinoma Prognosis after Curative Resection. J Oncol 2018;2018:9289421 View Article PubMed/NCBI
  140. Sorop A, Constantinescu D, Cojocaru F, Dinischiotu A, Cucu D, Dima SO. Exosomal microRNAs as Biomarkers and Therapeutic Targets for Hepatocellular Carcinoma. Int J Mol Sci 2021;22(9):4997 View Article PubMed/NCBI
  141. Conigliaro A, Costa V, Lo Dico A, Saieva L, Buccheri S, Dieli F, et al. CD90+ liver cancer cells modulate endothelial cell phenotype through the release of exosomes containing H19 lncRNA. Mol Cancer 2015;14:155 View Article PubMed/NCBI
  142. Wang S, Xu M, Li X, Su X, Xiao X, Keating A, et al. Exosomes released by hepatocarcinoma cells endow adipocytes with tumor-promoting properties. J Hematol Oncol 2018;11(1):82 View Article PubMed/NCBI
  143. Miyazoe Y, Miuma S, Miyaaki H, Kanda Y, Nakashiki S, Sasaki R, et al. Extracellular vesicles from senescent hepatic stellate cells promote cell viability of hepatoma cells through increasing EGF secretion from differentiated THP-1 cells. Biomed Rep 2020;12(4):163-170 View Article PubMed/NCBI
  144. Das D, Fayazzadeh E, Li X, Koirala N, Wadera A, Lang M, et al. Quiescent hepatic stellate cells induce toxicity and sensitivity to doxorubicin in cancer cells through a caspase-independent cell death pathway: Central role of apoptosis-inducing factor. J Cell Physiol 2020;235(9):6167-6182 View Article PubMed/NCBI
  145. Li J, Yan Y, Ang L, Li X, Liu C, Sun B, et al. Extracellular vesicles-derived OncomiRs mediate communication between cancer cells and cancer-associated hepatic stellate cells in hepatocellular carcinoma microenvironment. Carcinogenesis 2020;41(2):223-234 View Article PubMed/NCBI
  146. Beyoglu D, Idle JR. Metabolomic and Lipidomic Biomarkers for Premalignant Liver Disease Diagnosis and Therapy. Metabolites 2020;10(2):50 View Article PubMed/NCBI
  147. Gim JA, Bang SM, Lee YS, Lee Y, Yim SY, Jung YK, et al. Evaluation of the severity of nonalcoholic fatty liver disease through analysis of serum exosomal miRNA expression. PLoS One 2021;16(8):e0255822 View Article PubMed/NCBI
  148. Wang D, Huang T, Ren T, Liu Q, Zhou Z, Ge L, et al. Identification of Blood Exosomal miRNA-1246, miRNA-150-5p, miRNA-5787 and miRNA-8069 as Sensitive Biomarkers for Hepatitis B Virus Infection. Clin Lab 2022;68(2) View Article PubMed/NCBI
  149. Wang Q, Hu Q, Ying Y, Lu C, Li W, Huang C, et al. Using Next-generation Sequencing to Identify Novel Exosomal miRNAs as Biomarkers for Significant Hepatic Fibrosis. Discov Med 2021;31(164):147-159 View Article PubMed/NCBI
  150. Wei XC, Liu LJ, Zhu F. Exosomes as potential diagnosis and treatment for liver cancer. World J Gastrointest Oncol 2022;14(1):334-347 View Article PubMed/NCBI
  151. Ma L, Wei J, Zeng Y, Liu J, Xiao E, Kang Y, et al. Mesenchymal stem cell-originated exosomal circDIDO1 suppresses hepatic stellate cell activation by miR-141-3p/PTEN/AKT pathway in human liver fibrosis. Drug Deliv 2022;29(1):440-453 View Article PubMed/NCBI
  152. Dai X, Chen C, Xue J, Xiao T, Mostofa G, Wang D, et al. Exosomal MALAT1 derived from hepatic cells is involved in the activation of hepatic stellate cells via miRNA-26b in fibrosis induced by arsenite. Toxicol Lett 2019;316:73-84 View Article PubMed/NCBI
  153. Wang W, Li F, Lai X, Liu H, Wu S, Han Y, et al. Exosomes secreted by palmitic acid-treated hepatocytes promote LX-2 cell activation by transferring miRNA-107. Cell Death Discov 2021;7(1):174 View Article PubMed/NCBI
  154. Feng T, Fang F, Zhang C, Li T, He J, Shen Y, et al. Fluid Shear Stress-Induced Exosomes from Liver Cancer Cells Promote Activation of Cancer-Associated Fibroblasts via IGF2-PI3K Axis. Front Biosci (Landmark Ed) 2022;27(3):104 View Article PubMed/NCBI
  155. Li F, Zhan L, Dong Q, Wang Q, Wang Y, Li X, et al. Tumor-Derived Exosome-Educated Hepatic Stellate Cells Regulate Lactate Metabolism of Hypoxic Colorectal Tumor Cells via the IL-6/STAT3 Pathway to Confer Drug Resistance. Onco Targets Ther 2020;13:7851-7864 View Article PubMed/NCBI
  156. Xia Y, Zhen L, Li H, Wang S, Chen S, Wang C, et al. MIRLET7BHG promotes hepatocellular carcinoma progression by activating hepatic stellate cells through exosomal SMO to trigger Hedgehog pathway. Cell Death Dis 2021;12(4):326 View Article PubMed/NCBI

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