Related Experiment Video
Updated: May 10, 2026
09:12
A Mouse Model of Chronic Liver Fibrosis for the Study of Biliary Atresia
Published on: February 3, 2023
Biliary epithelial senescence and plasticity in acute cellular rejection
J G Brain1, H Robertson, E Thompson
1Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Summary
Biliary epithelial cells (BEC) in liver allografts can undergo senescence or de-differentiation during rejection. Oxidative stress induces TGF-β2, driving BEC de-differentiation, which may impair allograft function.
Area of Science:
- Hepatology
- Transplantation Immunology
- Cell Biology
Background:
- Biliary epithelial cells (BEC) are crucial in liver health and disease, particularly during acute allograft rejection.
- Injured BEC can enter states of senescence or phenotypic de-differentiation, impacting liver function.
- Understanding BEC phenotypic changes during rejection is vital for improving transplant outcomes.
Purpose of the Study:
- To investigate the phenotypic alterations of BEC during acute liver allograft rejection.
- To elucidate the underlying mechanisms driving these BEC changes, focusing on senescence and de-differentiation.
- To explore the role of transforming growth factor-beta (TGF-β) in BEC modulation.
Main Methods:
- Analysis of liver allograft sections to correlate rejection severity with BEC senescence and mesenchymal marker expression.
- In vitro modeling using primary or immortalized BEC subjected to acute oxidative stress.
- Assessment of p21(WAF1/Cip) and S100A4 expression as markers of senescence and mesenchymal phenotype.
- Quantification of TGF-β isoforms (mRNA and protein) following oxidative stress.
- Pharmacological inhibition of the TGF-β receptor (ALK-5) to assess its role in epithelial de-differentiation.
Main Results:
- A significant positive correlation was observed between T cell-mediated acute rejection and the expression of p21(WAF1/Cip) and S100A4 in BEC.
- In vitro, oxidative stress induced transient p21(WAF1/Cip) expression followed by increased mesenchymal markers and decreased epithelial markers in BEC.
- Oxidative stress led to a rapid increase in TGF-β2 at both mRNA and protein levels.
- Blocking the ALK-5 receptor abrogated the observed epithelial de-differentiation in vitro.
Conclusions:
- Acute liver allograft rejection is associated with BEC senescence and a shift towards a mesenchymal phenotype.
- Stress-induced TGF-β2 production by BEC plays a key role in driving epithelial de-differentiation.
- Targeting the TGF-β pathway may offer a therapeutic strategy to preserve BEC phenotype and improve liver allograft function.
Related Concept Videos
01:21Chronic Pancreatitis II: Pathophysiology
Chronic pancreatitis is a progressive and irreversible inflammation of the pancreas, most often caused by long-term alcohol abuse, but it can also be related to ductal obstruction, smoking, or genetic factors.Chronic pancreatitis occurs when the pancreas is repeatedly exposed to harmful agents like alcohol, smoking, ductal obstruction, or genetic predisposition. These factors lead to the release of toxic metabolites and inflammatory cytokines, sustaining chronic inflammation in the pancreatic...
01:24Liver Regeneration
The liver is an important organ in vertebrates that plays an essential role in metabolism. It is also responsible for storing and redistributing nutrients such as carbohydrates, fats, and vitamins in the body. Additionally, the liver releases bile salts which are critical for digesting food and eliminating toxic metabolites from the body.
Cells of Liver
The liver comprises four major types of cells— hepatocytes, stellate, Kupffer, and sinusoidal endothelial cells. The hepatocytes are large...
Cells of Liver
The liver comprises four major types of cells— hepatocytes, stellate, Kupffer, and sinusoidal endothelial cells. The hepatocytes are large...
01:23Tissue Renewal without Stem Cells
After cellular or tissue damage, the resident stem cells present in the human body can locally repair and regenerate the damaged tissue or organ. However, even though some tissues do not have stem cells, they can repair and regenerate with the help of pre-existing cells. For example, beta cells of the pancreas and hepatocytes of the liver can divide to renew and regenerate the tissue. Here, both cell division and cell death are well regulated by homeostasis.
However, failure of such a system...
However, failure of such a system...
01:24Cirrhosis II: Pathophysiology
Cirrhosis is a progressive chronic liver injury caused by prolonged inflammation, excessive fibrotic remodeling, and impaired regeneration. Over time, repeated hepatic insults disrupt the liver’s architecture and function, leading to reduced blood flow, impaired bile drainage, and diminished metabolic capacity.Pathophysiology of cirrhosisCirrhosis arises from three main responses to chronic liver damage: inflammation, immune activation, and hepatocyte death. These processes lead to structural...
01:40Cell-mediated Immune Responses
Overview
01:25Chronic Pancreatitis I: Introduction
Chronic pancreatitis is a long-standing, relapsing inflammation of the pancreas, characterized by irreversible damage to the gland. It results in progressive destruction of the pancreatic parenchyma, fibrosis, and eventual loss of both exocrine and endocrine function. The disease may evolve gradually after multiple episodes of acute pancreatitis or develop independently.EtiologyChronic pancreatitis can arise from a variety of causes:Alcohol use is the leading cause, accounting for 70–80% of...