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Old Livers Made New Again

Unhealthy organs provide a framework for growing replacement ones.

Scientists at Massachusetts General Hospital in Boston have taken the first steps toward building functional, transplantable livers. In a study in rats, published online today by Nature Medicine, the researchers took donor livers, gently stripped them of their cells while leaving other material intact, and then used the remaining structure as a scaffold on which to grow healthy liver cells. The result was a nearly complete organ that was transplanted into the rats and remained functional for up to eight hours.

Before and after: Scientists are using unhealthy rat livers, such as the one shown on the left, to rebuild functioning ones. Washing away the old cells and their debris with a detergent leaves a scaffold that retains its blood-vessel architecture, shown at right. The new scaffold can then be seeded with healthy liver cells.

Liver disease is the 12th-largest cause of death in the United States, while heart and kidney disease rank even higher. The symptoms of organ failure can be treated to some extent, but the only cure is transplantation, and there just aren’t enough healthy donor organs to go around. For decades, researchers have been working to build replacements. But organs are complex systems, with a cell density and blood-vessel system that are difficult to replicate.

The new technique, which was first demonstrated in hearts two years ago, takes advantage of an organ’s preexisting structure in all its intricacy, and provides a use for unhealthy organs that could not otherwise be used. “We try to resuscitate organs that would be discarded and do things to make them transplantable,” says Basak Uygun, the paper’s first author and a researcher at the Center for Engineering in Medicine at MGH.

Other approaches for organ regeneration have varied widely, from creating lab-made scaffolds to using ink-jet printers to create three-dimensional tissue. But all of these methods try to mimic what the body has already successfully created. The “decellularization” technique capitalizes on that, removing what’s broken and replacing it with healthy new cells. “What we’ve done is basically take the shortcut,” says Korkut Uygun, the researcher at the Center for Engineering in Medicine who led the work.

“This leapfrogs other approaches,” says Stephen Badylak, a specialist in tissue engineering at the University of Pittsburgh’s McGowan Center for Regenerative Medicine. “The beauty of this approach is that it doesn’t try to synthesize anything. It tries to isolate Mother Nature’s three-dimensional scaffold and take advantage of that. If this can be translated to the clinic–and we’re still a ways away from that–it’s a tremendous advance.”

Uygun and her colleagues started with livers from rat that had died from oxygen deprivation. They decellularized the livers with a detergent, which killed off the remaining cells and removed their debris. What remained was a delicate scaffold of proteins and sugars and other extracellular structures, including blood vessel architecture–the most complex aspect of the liver, the hardest to duplicate, and the one most necessary for the survival of the new cells. The scientists seeded the scaffold with liver cells isolated from healthy rat livers, as well as endothelial cells to line the blood vessels, and the result remained functional in culture for 10 days.

Liver basting: After a scaffold is seeded with healthy liver cells, it is placed in an in vitro culture setup. The pink liquid circulating in the scaffold has the required nutrients to keep the cells alive. The scaffold has not yet been seeded with healthy cells.

The researchers also transplanted two-day-old reconstructed livers back into rats, connecting them to the animals’ vascular system. After eight hours, the livers continued to incorporate the animals’ blood flow and remained functional, something that had never before been done with such a complicated engineered organ. “It is very promising approach that will revolutionize the field of tissue engineering for livers,” Basak Uygun says. It’s a particularly challenging organ, because it requires constant and extensive blood circulation. “So if this could be done for livers, it’s major progress.”

“It’s very good work and it advances the field, showing more and more that these things can in fact be done and are possible,” says Anthony Atala, director of the Institute for Regenerative Medicine at Wake Forest University Baptist Medical Center, who has used both the ink-jet printing and decellularization approach. “Solid organs are incredibly complex, because they have a lot more cells per centimeter than any other tissue type. And how do you get blood supply to such a large volume of cells? Decellularized organs are a good strategy for preserving vascular tissue.”

There are, however, a few big obstacles remaining. The first problem is that the current method can’t quite repopulate the blood vessels densely enough to allow blood circulation for more than 24 hours. The exposed collagen of the scaffold causes the blood to coagulate and clot, which is why Uygun left the engineered livers transplanted for only eight hours.

The second obstacle will be finding a steady source for healthy human liver cells. In the nearer term, the researchers believe they can rely on cells from healthy donors. (Healthy livers can regenerate back to full size within just a few weeks.) But further down the line, stem-cell science may be advanced enough for people to donate their own cells, allowing scientists to differentiate them in the lab into liver cells that won’t induce an immune-system reaction and use those to seed a scaffold.

Korkut Uygun and his colleagues are already working on a solution to the blood-vessel problem, and believe they should have fully functional liver transplants in rats within two years. “We’re hoping it will be in the clinic in five to 10 years,” he says. “That’s assuming nothing goes wrong.”

It’s a tantalizing prospect. “This represents a potential therapy for those patients who aren’t fortunate enough to get a transplant or aren’t eligible for one,” Badylak says. “It’s a terrific step forward.”

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