Published online Feb 27, 2021. doi: 10.4254/wjh.v13.i2.187
Peer-review started: August 26, 2020
First decision: October 21, 2020
Revised: November 4, 2020
Accepted: December 30, 2020
Article in press: December 30, 2020
Published online: February 27, 2021
Processing time: 182 Days and 5.2 Hours
Liver fibrosis can result in end-stage liver failure and death.
To examine human liver fibrogenesis and anti-fibrotic therapies, we evaluated the three dimensional ex vivo liver slice (LS) model.
Fibrotic liver samples (F0 to F4 fibrosis stage according to the METAVIR score) were collected from patients after liver resection. Human liver slices (HLS) were cultivated for up to 21 days. Hepatitis C virus (HCV) infection, alcohol (ethanol stimulation) and steatosis (palmitate stimulation) were examined in fibrotic (F2 to F4) liver slices infected (or not) with HCV. F0-F1 HLS were used as controls. At day 0, either ursodeoxycholic acid (choleretic and hepatoprotective properties) and/or α-tocopherol (antioxidant properties) were added to standard of care on HLS and fibrotic liver slices, infected (or not) with HCV. Expression of the biomarkers of fibrosis and the triglyceride production were checked by quantitative reverse transcription polymerase chain reaction and/or enzyme-linked immunosorbent assay.
The cultures were viable in vitro for 21 days allowing to study fibrosis inducers and to estimate the effect of anti-fibrotic drugs. Expression of the biomarkers of fibrosis and the progression to steatosis (estimated by triglycerides production) was increased with the addition of HCV and /or ethanol or palmitate. From day 15 of the follow-up studies, a significant decrease of both transforming growth factor β-1 and Procol1A1 expression and triglycerides production was observed when a combined anti-fibrotic treatment was applied on HCV infected F2-F4 LS cultures.
These results show that the human three dimensional ex vivo model effectively reflects the in vivo processes in damaged human liver (viral, alcoholic, nonalcoholic steatohepatitis liver diseases) and provides the proof of concept that the LS examined model permits a rapid evaluation of new anti-fibrotic therapies when used alone or in combination.
Core Tip: In the developed world, about 45% of deaths are due to fibroproliferative diseases. Liver fibrosis is frequently associated with viral infection (Hepatitis C virus and Hepatitis B virus infection), chronic inflammation and excessive alcohol consumption. Despite the availability of effective antiviral drugs, morbidity, and mortality related to viral hepatitis are still increasing. Moreover, the number of non-viral liver diseases such as nonalcoholic steatohepatitis, and alcoholic liver disease is steadily growing. Our studies provide the proof of concept that the three-dimensional ex vivo model of human liver slice culture can be used for the molecular investigation of fibrosis as well as to perform follow-up studies of new anti-fibrotic drugs and therapies for a 21-days period.