Can we use animals as living incubators for human tissue?

Author: Jovana Drinjakovic, 01/16/17

Human liver cells grown in pigs could be used in future transplants. Photo credit: By Guido Gerding – Personal photograph taken by Author, URL: Ex :: Natura – Freies Portal für Umweltbildung (Environmental Education), CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=3872502

Markus Grompe certainly thinks so and is working hard to make it happen. A scientist and a pediatrician specializing in inborn liver diseases, Dr. Grompe has a plan for overcoming the shortage of organ donors—the key obstacle for patients for whom the liver transplant is the only hope.

Based at the Oregon Health and Science University, Dr. Grompe has successfully developed a technology that allows him to grow human liver tissue in mice. He presented the work, including current efforts to do the same in pigs, at the inaugural Medicine by Design symposium in Toronto, which took place on November 28, 2016. (More on growing organs inside pigs for human transplants here and here. You will notice a theme.)

Approximately one in three patients on the waiting list for transplants will die due to a shortage of donor organs, according to the Canadian Liver Foundation. But for some diseases, the entire organ replacement may not even be necessary – restoring only a portion of a diseased tissue may be enough to save a person’s life. It’s no wonder that scientists across the globe are working to create replacement tissue from stem cells in a dish. Although promising, this approach has its challenges.

Stem cells don’t just have the ability to turn into every cell type; they also divide without end. One difficulty, then, is to ensure that a stem-cell derived tissue graft holds no remaining stem cells, which could turn into cancer. Another challenge is to produce a graft containing billions of cells—of the highest quality—that would be required for a single transplant.

And as if these hurdles weren’t big enough, some cells just won’t grow despite researchers’ best attempts to mimic their natural environment in a dish. This is the case with hepatocytes: cells that make up the bulk of the liver and degrade toxic products of metabolism.

For reasons that are not fully understood, hepatocytes can’t be coaxed to multiply outside of the body, which means that it hasn’t been possible to create a lab-grown tissue substitute for future use in treating liver disease.

Yet transplanted hepatocytes have shown promise in healing damaged livers in patients who received donated cell grafts. These cadaveric hepatocyte transplants helped stave off liver failure until the whole organ became available for the transplant, or, in some cases, even skirted the need for the transplant altogether.

In contrast to their poor growth in the dish, hepatocytes readily multiply in the liver, helping it regenerate through a person’s lifetime. With this in mind, Dr. Grompe wondered if human hepatocytes could be expanded in the liver of an animal, from which they could be harvested for future transplants.

He calls this “hepatocyte farming.”

Dr. Grompe’s research

He first tested the idea in mice by genetically engineering animals whose livers would become a rich soil for the human hepatocytes to grow on. The mice were created to lack a key liver enzyme that degrades the amino acid tyrosine. In its absence, the mice develop tyrosinemia, a disease where the toxic tyrosine pile-up kills the cells and leads to liver failure. Like a pesticide clearing the ground of unwanted weeds, the missing enzyme ensures that mouse cells die off. While the engineered mice die before birth, the disease can be stalled with the nitisinone drug, also given to human patients, allowing the animals to survive until they receive the graft containing human hepatocytes. By withdrawing nitisinone after the transplant, the mice are left to the mercy of human cells to restore their failing livers.

Dr. Grompe reported that not only did the human cells successfully multiply in the mouse liver, they also replaced the diseased mouse cells to take over the entire organ, creating mice with human-like livers. What’s more, human cells from one mouse could be serially transplanted into other animals without causing tumours or losing their ability to regenerate the liver. This means that through repeated rounds of transplants, a small starting material of human hepatocytes (about five million of them) can quickly mushroom to trillions of cells, according to Dr. Grompe, whose company Yakuris has commercialized the approach.

Mice are alright but pigs are better—their livers are bigger and roughly the same size as ours. Recently, Dr. Grompe’s team successfully created a pig with tyrosinemia in the hope of boosting the yield of human liver cells.

That’s not to say that the animal-grown human hepatocytes are anywhere close to being ready for transplants. One major concern is left-over animal cells that harbour DNA viruses that can cause mutations and spur cancer. However scarce these remaining cells may be, transplanting animal cells into humans could be catastrophic.

In the meantime, farmed human hepatocytes will continue to be used in research, helping scientists understand the molecular basis of liver disease and test drugs.

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Jovana Drinjakovic

Jovana Drinjakovic

Jovana Drinjakovic is a science writer with a background in cell and developmental biology. After completing her PhD in Cambridge (the old one) and a postdoc at the Hospital for Sick Children in Toronto, Jovana decided to switch gears and enrolled into a journalism course at the University of Toronto’s Munk School of Global Affairs. Her writing appeared in the Globe and Mail, the National Post, Dallas Morning News and U of T Magazine. Most days Jovana writes about discoveries at U of T’s Donnelly Centre, where she works as a communication specialist.
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