Bile duct organoids help repair human livers
Cell-based therapies could provide an advantageous alternative, but 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.
Scientists were able to use lab grown bile ducts to repair damaged mouse livers and in donor human livers cultured outside of the body demonstrating, for the first time, that that lab grown organoids could be used in regenerative medicine to repair damaged donor organs making liver transplants more accessible – more work needs to be done before this can move to the clinic though.
Bile ducts act as the liver’s waste disposal system, and malfunctioning bile ducts are behind a third of adult and 70 percent of children’s liver transplantations—there are currently no alternative treatments, which is a problem given the shortage of liver donors.
Cell-based therapies could provide an advantageous alternative, but 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 in Science, scientists at the University of Cambridge have described 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 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 other 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 Fotios Sampaziotis of 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 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. They then grafted these gallbladder organoids into mice and found that they could repair damaged ducts, opening 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.
“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,” said Ludovic Vallier from the Wellcome-MRC Cambridge Stem Cell Institute. “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.”
