Lab-grown 'mini-bile ducts' used to repair human livers in regenerative medicine first

February 18, 2021

Scientists have used a technique to grow bile duct organoids - often referred to as 'mini-organs' - in the lab and shown that these can be used to repair damaged human livers. This is the first time that the technique has been used on human organs.

The research paves the way for cell therapies to treat liver disease - in other words, growing 'mini-bile ducts' in the lab as replacement parts that can be used to restore a patient's own liver to health - or to repair damaged organ donor livers, so that they can still be used for transplantation.

Bile ducts act as the liver's waste disposal system, and malfunctioning bile ducts are behind a third of adult and 70 per cent of children's liver transplantations, with no alternative treatments. There is currently a shortage of liver donors: according to the NHS, the average waiting time for a liver transplant in the UK is 135 days for adults and 73 days for children. This means that only a limited number of patients can benefit from this therapy.

Approaches to increase organ availability or provide an alternative to whole organ transplantation are urgently needed. Cell-based therapies could provide an advantageous alternative. However, the development of these new therapies is often impaired and delayed by the lack of an appropriate model to test their safety and efficacy in humans before embarking in clinical trials.

Now, in a study published today in Science, scientists at the University of Cambridge have developed a new approach that takes advantage of a recent 'perfusion system' that can be used to maintain donated organs outside the body. Using this technology, they demonstrated for the first time that it is possible to transplant biliary cells grown in the lab known as cholangiocytes into damaged human livers to repair them. As proof-of-principle for their method, they repaired livers deemed unsuitable for transplantation due to bile duct damage. This approach could be applied to a diversity of organs and diseases to accelerate the clinical application of cell-based therapy.

"Given the chronic shortage of donor organs, it's important to look at ways of repairing damaged organs, or even provide alternatives to organ transplantation," said Dr Fotios Sampaziotis from the Wellcome-MRC Cambridge Stem Cell Institute. "We've been using organoids for several years now to understand biology and disease or their regeneration capacity in small animals, but we have always hoped to be able to use them to repair human damaged tissue. Ours is the first study to show, in principle, that this should be possible."

Bile duct diseases affect only certain ducts while sparing others. This is important because in disease, the ducts in need of repair are often fully destroyed and cholangiocytes may be harvested successfully only from spared ducts.

Using the techniques of single-cell RNA sequencing and organoid culture, the researchers discovered that, although duct cells differ, biliary cells from the gallbladder, which is usually spared by the disease, could be converted to the cells of the bile ducts usually destroyed in disease (intrahepatic ducts) and vice versa using a component of bile known as bile acid. This means that the patient's own cells from disease-spared areas could be used to repair destroyed ducts.

To test this hypothesis, the researchers grew gallbladder cells as organoids in the lab. Organoids are clusters of cells that can grow and proliferate in culture, taking on a 3D structure that has the same tissue architecture, function and gene expression and genetic functions as the part of the organ being studied. They then grafted these gallbladder organoids into mice and found that they were indeed able to repair damaged ducts, opening up avenues for regenerative medicine applications in the context of diseases affecting the biliary system.

The team used the technique on human donor livers taking advantage of the perfusion system used by researchers based at Addenbrooke's Hospital, part of Cambridge University Hospitals NHS Foundation. They injected the gallbladder organoids into the human liver and showed for the first time that the transplanted organoids repaired the organ's ducts and restored their function. This study therefore confirmed that their cell-based therapy could be used to repair damaged livers.

Professor Ludovic Vallier from the Wellcome-MRC Cambridge Stem Cell Institute, joint senior author, said: "This is the first time that we've been able to show that a human liver can be enhanced or repaired using cells grown in the lab. We have further work to do to test the safety and viability of this approach, but hope we will be able to transfer this into the clinic in the coming years."

Although the researchers anticipate this approach being used to repair a patient's own liver, they believe it may also offer a potential way of repairing damaged donor livers, making them suitable for transplant.

Mr Kourosh Saeb-Parsy from the Department of Surgery at the University of Cambridge, joint senior author, added: "This is an important step towards allowing us to use organs previously deemed unsuitable for transplantation. In future, it could help reduce the pressure on the transplant waiting list."
-end-
The research was supported by the European Research Council, the National Institute for Health Research and the Academy of Medical Sciences.

Reference

Sampaziotis, F et al. Cholangiocyte organoids can repair bile ducts after transplantation in human liver. Science; 19 Feb 2021

University of Cambridge

Related Transplantation Articles from Brightsurf:

A revolutionary new treatment alternative to corneal transplantation
A new approach in ophthalmology that offers a revolutionary alternative to corneal transplantation has just been developed by researchers and clinicians in North America, Europe, and Oceania.

Fewer complications after organ transplantation
A large international study coordinated by University Hospital Regensburg and Charité - Universitätsmedizin Berlin has demonstrated the safety of new cell therapy approaches for use in kidney transplant recipients.

Elderly patients also benefit from kidney transplantation
So far, kidney transplantation has generally not been offered to elderly patients (>75 years) because of the perioperative risks.

New material will allow abandoning bone marrow transplantation
Scientists from the National University of Science and Technology 'MISIS' developed nanomaterial, which will be able to restore the internal structure of bones damaged due to osteoporosis and osteomyelitis.

Fewer medical tests -- timely listing for transplantation
Younger patients would benefit greatly from kidney transplantation. Their expected remaining lifetime may even be doubled by having a transplant.

Uterus transplantation -- ethically just as problematic as altruistic surrogacy
In 2014, the first child to have been gestated in a donated uterus was born.

Advancing transplantation: Hepatitis C-infected organs safe for transplantation when followed by antiviral treatment
Twenty patients at Penn Medicine have been cured of the hepatitis C virus (HCV) following lifesaving kidney transplants from deceased donors who were infected with the disease, according to a study published today in Annals of Internal Medicine.

Transplantation followed by antiviral therapy cured hepatitis C
Twenty patients who received kidneys transplanted from hepatitis C virus (HCV)-infected donors experienced HCV cure, good quality of life, and excellent renal function at one year.

The Journal of Heart and Lung Transplantation: 50 years of heart transplantation progress
This month marks the 50th anniversary of the world's first human heart transplant performed at Groote Schuur Hospital in Cape Town by South African surgeon, Christiaan Barnard.

Older donor lungs should be considered for transplantation
With a scarcity of lungs available for transplantation, the use of lungs from donors older than age 60 has been shown to achieve reasonable outcomes and should be considered as a viable option, according to research published online today in The Annals of Thoracic Surgery.

Read More: Transplantation News and Transplantation Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.