Molecular and cellular mechanisms of liver fibrosis and its regression

Kisseleva, Tatiana; Brenner, David A.

doi:10.1038/s41575-020-00372-7

Cited by 999 publications

(980 citation statements)

References 266 publications

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“…Hepatic tissue's regenerative capacity safeguards the liver from acute injury even when a significant part of the liver is damaged or excised [ 1 ]. Liver is capable of restoring its histology and physiology during the process of regeneration.…”

Section: Introductionmentioning

confidence: 99%

“…The wound healing process is instrumental in acute liver injuries; however, in the case of chronic liver pathologies, scar tissue disintegrates the liver parenchyma, interrupt blood flow, and eventually results in disruption of cohesive cell–cell tight junction proteins (TJPs) [ 2 , 3 ]. The scar tissue is mainly composed of the extracellular matrix (ECM) proteins collagens, proteoglycans, and glycoproteins, especially cross-linked collagen type I and type III [ 1 ]. Its abnormal aggregation is called liver fibrosis.…”

Section: Introductionmentioning

confidence: 99%

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Real-time monitoring of liver fibrosis through embedded sensors in a microphysiological system

et al. 2021

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Hepatic fibrosis is a foreshadowing of future adverse events like liver cirrhosis, liver failure, and cancer. Hepatic stellate cell activation is the main event of liver fibrosis, which results in excessive extracellular matrix deposition and hepatic parenchyma's disintegration. Several biochemical and molecular assays have been introduced for in vitro study of the hepatic fibrosis progression. However, they do not forecast real-time events happening to the in vitro models. Trans-epithelial electrical resistance (TEER) is used in cell culture science to measure cell monolayer barrier integrity. Herein, we explored TEER measurement's utility for monitoring fibrosis development in a dynamic cell culture microphysiological system. Immortal HepG2 cells and fibroblasts were co-cultured, and transforming growth factor β1 (TGF-β1) was used as a fibrosis stimulus to create a liver fibrosis-on-chip model. A glass chip-based embedded TEER and reactive oxygen species (ROS) sensors were employed to gauge the effect of TGF-β1 within the microphysiological system, which promotes a positive feedback response in fibrosis development. Furthermore, albumin, Urea, CYP450 measurements, and immunofluorescent microscopy were performed to correlate the following data with embedded sensors responses. We found that chip embedded electrochemical sensors could be used as a potential substitute for conventional end-point assays for studying fibrosis in microphysiological systems.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Real-time monitoring of liver fibrosis through embedded sensors in a microphysiological system

et al. 2021

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“…There is a consensus that liver fibrosis is the healing response of the liver to chronic injuries, including hepatitis, immune compounds and drugs ( 28 ). Generally, hepatitis B remains a major health concern worldwide, infecting ~350 million patients ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

“…Liver fibrosis is characterized by excessive deposition of ECM in the liver, with ensuing destruction of the liver architecture ( 28 ). HSCs are the main sources of ECM, and their activation has been considered as a key event in liver fibrosis ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

HBV induces liver fibrosis via the TGF‑β1/miR‑21‑5p pathway

Chen

et al. 2020

Exp Ther Med

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MicroRNA (miR)-21-5p is a newly discovered factor that mediates TGF-β1 signaling. The present study was designed to investigate the role of TGF-β1/miR-21-5p in hepatitis B virus (HBV)-induced liver fibrosis. HBV-infected sodium taurocholate co -t ra nspor ting polypeptide (NTCP)-transfected Huh7.5.1 cells were co-cultured with LX2 cells to simulate HBV infection in the present study. A total of 29 patients with chronic HBV infection were enrolled. Cells were transfected with miR-21-5p mimic or inhibitor with or without TGF-β1 stimulation. The demographic, biochemical and virological data from the 29 patients were analyzed and liver tissues were collected. miR-21-5p levels and the mRNA and protein expression of α-smooth muscle actin (SMA), collagen type 1 α 1 (CoL1A1), tissue inhibitor of metalloproteinase (TIMP)-1 and Smad from liver cells or tissues were detected by quantitative PCR analysis and western blotting, respectively. Cell viability was observed, and the liver fibrosis score was evaluated. The association between miR-21-5p and liver fibrosis was evaluated by correlation analysis. HBV infection upregulated TGF-β1/miR-21-5p mRNA expression in NTCP-Huh7.5.1 cells compared with mock infection (P<0.05). TGF-β1 incubation significantly increased miR-21-5p levels, as well as the mRNA and protein expression of α-SMA, CoL1A1 and TIMP-1, and reduced Smad7 expression in LX2 cells compared with the normal group, and these effects were counteracted by miR-21-5p inhibitor (P<0.05). miR-21-5p overexpression also contributed to TGF-β1-induced α-SMA, CoL1A1 and TIMP-1 expression in LX2 cells (P<0.05). Co-culture with HBV-infected NTCP-Huh7.5.1 cells upregulated TGF-β1/miR-21-5p activity and CoL1A1 expression in LX2 cells compared with normal control, which were significantly reduced by miR-21-5p inhibitor (P<0.05). miR-21-5p levels were significantly correlated with the liver fibrosis score (r=0.888; P<0.05). These data demonstrated that HBV induced liver fibrosis via the TGF-β1/miR-21-5p pathway and suggested that miR-21-5p may be an effective anti-fibrosis target.

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“…However, the downstream signaling pathways requires further experimental clarification. In addition, fibrogenesis not only involves collagen production but also many molecular and cellular mechanisms[ 55 ]. The co-operation of the TLR4-MyD88 pathway with other signaling pathways, such as TGF-β signaling and inflammatory response, also requires further investigation to determine their relative contributions to liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Extracellular histones stimulate collagen expressionin vitroand promote liver fibrogenesis in a mouse modelviathe TLR4-MyD88 signaling pathway

Wang

Cheng

Abrams

et al. 2020

WJG

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BACKGROUND Liver fibrosis progressing to liver cirrhosis and hepatic carcinoma is very common and causes more than one million deaths annually. Fibrosis develops from recurrent liver injury but the molecular mechanisms are not fully understood. Recently, the TLR4-MyD88 signaling pathway has been reported to contribute to fibrosis. Extracellular histones are ligands of TLR4 but their roles in liver fibrosis have not been investigated. AIM To investigate the roles and potential mechanisms of extracellular histones in liver fibrosis. METHODS In vitro , LX2 human hepatic stellate cells (HSCs) were treated with histones in the presence or absence of non-anticoagulant heparin (NAHP) for neutralizing histones or TLR4-blocking antibody. The resultant cellular expression of collagen I was detected using western blotting and immunofluorescent staining. In vivo , the CCl 4 -induced liver fibrosis model was generated in male 6-week-old ICR mice and in TLR4 or MyD88 knockout and parental mice. Circulating histones were detected and the effect of NAHP was evaluated. RESULTS Extracellular histones strongly stimulated LX2 cells to produce collagen I. Histone-enhanced collagen expression was significantly reduced by NAHP and TLR4-blocking antibody. In CCl 4 -treated wild type mice, circulating histones were dramatically increased and maintained high levels during the duration of fibrosis-induction. Injection of NAHP not only reduced alanine aminotransferase and liver injury scores, but also significantly reduced fibrogenesis. Since the TLR4-blocking antibody reduced histone-enhanced collagen I production in HSC, the CCl 4 model with TLR4 and MyD88 knockout mice was used to demonstrate the roles of the TLR4-MyD88 signaling pathway in CCl 4 -induced liver fibrosis. The levels of liver fibrosis were indeed significantly reduced in knockout mice compared to wild type parental mice. CONCLUSION Extracellular histones potentially enhance fibrogenesis via the TLR4–MyD88 signaling pathway and NAHP has therapeutic potential by detoxifying extracellular histones.

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Molecular and cellular mechanisms of liver fibrosis and its regression

Cited by 999 publications

References 266 publications

Real-time monitoring of liver fibrosis through embedded sensors in a microphysiological system

Real-time monitoring of liver fibrosis through embedded sensors in a microphysiological system

HBV induces liver fibrosis via the TGF‑β1/miR‑21‑5p pathway

Extracellular histones stimulate collagen expressionin vitroand promote liver fibrogenesis in a mouse modelviathe TLR4-MyD88 signaling pathway

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