March 3rd 2021
America is facing a national organ crisis with over 109,000 men, women and children on the organ transplant waiting list—a new person is added to that list every 9 minutes. Organ transplants have always been complicated due to high organ rejection rates and a limited donor supply; yet major breakthroughs in transplant science and immunosuppression (which decreases rejection rates) are a direct benefit of research in non-human animals (e.g., here).
According to the United Network for Organ Sharing (UNOS), the nonprofit that manages the national organ transplant system, there were 39,035 transplant operations in the U.S. in 2020, down from a record 39,718 in 2019—remarkable numbers given the many challenges presented by the pandemic. Unfortunately, these challenges will only increase, given for example, the first case of COVID-19 infection and death following an organ transplant.
How is animal research helping?
As we’ve written about previously, formative research into organ transplantation and immunosuppression using dogs, pigs and baboons paved the way for modern transplant medicine as we know it. Now, a new study, using mice as a proof-of-concept, has demonstrated that lab grown bile ducts can be used to repair human livers—a first in regenerative medicine.
Although the human liver is capable of regeneration (as you may know from Greek mythology and Prometheus), the bile ducts within can still be damaged, often making organ transplant necessary. Bile ducts act as the liver’s waste disposal system, and malfunctioning bile ducts underlie a third of adults and 70 percent of children liver transplants, with no alternative treatments. In the US alone, the liver is ranked second among transplanted organs. Without a substantial increase in organ donors, regenerative medicine may be the only solution to the organ shortage crisis. However, this solution has not been actively pursued due to lack of a reasonable model for safety and efficacy testing before clinical trials in humans can begin—until now.
Using a recently developed ‘perfusion system’ that can be used to maintain donated organs outside the body, researchers demonstrated for the first time that it is possible to transplant bile cells grown in the lab, known as cholangiocytes, into damaged human livers to repair and rejuvenate 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 increase the number of available organs for transplant, by rejuvenating tissue initially deemed unsuitable.
“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 [such as mice, rats and rabbits], 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.” [Emphases added]
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.
First, using the techniques of single-cell RNA sequencing and organoid culture, the researchers discovered that, although duct cells differ, bile cells from the gallbladder, usually spared by disease, could be converted into the bile duct cells (intrahepatic 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 then 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 bile system.
Next, the team used this 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.
Hopefully, we can soon use this cell-based therapy to repair and rejuvenate damaged organs within humans like was done in mice, and extend the perfusion system and cell-based therapy to other organs to continue building our organ banks with organs initially deemed unsuitable for transplant.
This research demonstrates nicely the integral role that animal research plays in human health and disease—from basic research involving organoids in small animals to evaluation of proof-of-principle and efficacy prior to moving to clinical trials. It is also an important reminder of the timescales that are needed from bench to bedside and the formative role that animal research plays in this process.
~Speaking of Research
*Taken from the press release from the University of Cambridge and edited for style and content.