Specialised sensory cell structures could be key to improved liver transplant success

Up to a quarter of people who receive a liver transplant experience bile duct complications, which can require further surgery or transplantation and even lead to death.  

A new study by the Stuart Forbes Research Group at the University’s Institute for Regeneration and Repair identified a potential intervention that may help reduce these complications. 

The research team showed that donor livers which go on to develop bile duct complications had shorter primary cilia – specialised hair-like signalling and sensory structures. 

Damage to the primary cilia results in cellular senescence, when cells age and stop dividing. 

Drugs targeting these aged cells were able to preserve the cilia, suggesting a potential method to reduce bile duct complications after transplant. 

Liver transplantation is the only curative option for many patients with end-stage liver disease, but patients often suffer bile duct complications following transplant. 

The bile duct is a tube that carries bile from the liver and gallbladder into the small intestine. 

After a liver has been donated, it is stored temporarily on ice with no blood supply. 

The primary cilia, which detect changes in bile flow and help cells communicate with each other, are vulnerable to damage during this time. 

The study showed that a longer time between liver collection and transplantation resulted in shorter primary cilia in the bile ducts. 

Long periods on ice can also lead to cellular senescence in the bile duct, when cells permanently stop dividing and growing, but do not die. 

Senescence prevents regeneration, and too many senescent cells can lead to problems like bleeding and blockages, inflammation or scar tissue formation. 

Senescence also impacts the primary cilia structure, triggering a negative feedback loop that further interferes with regeneration in the bile duct.

The researchers aimed to disrupt this cycle by protecting the primary cilia with a drug treatment. 

They treated tissue from human donor livers not suitable for transplant with senolytics, drugs that target and kill senescent cells, which successfully preserved the structure and length of the primary cilia in the bile duct. 

Their findings suggest that protecting the primary cilia by killing senescent cells may help prevent bile duct complications and improve outcomes for liver transplant patients. 

As well as conducting their research in mouse models, the researchers were able to investigate these findings in human bile ducts cells, by using tissue from livers unsuitable for donation and liver biopsies from transplant patients. 

The researchers also isolated human and mouse bile duct cells and used them to grow organoids - mini 3D cell cultures that mimic the complexity of the bile ducts, in a dish. 

This research was funded by the UK Medical Research Council (MRC), European Society for Organ Transplantation and Scottish Enterprise.

The research has been published in the Journal of Hepatology.

Stuart Forbes Research Group