Wake Forest University researchers engineer miniature human livers in the lab

Achievement is an early step to providing a solution to the shortage of livers available for patients needing transplants, as well as for potential drug discovery applications

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WINSTON-SALEM, N.C.—Researchers at Wake Forest University Baptist Medical Center have made what they call significant strides in the quest to grow replacement human livers, an important but early step to providing a solution to the shortage of livers available for patients needing transplants, as well as other potential drug discovery applications.

According to the researchers, who work at the university's Institute for Regenerative Medicine, there have been other successful efforts to engineer livers with animal cells, but they are the first to use human liver cells to engineer livers in the lab. They describe the process by which they achieved this in the study, "The Use of Whole Organ Decellularization for the Bioengineering of a Human Vascularized Liver," which will be published in an upcoming issue of the journal Hepatology. The researchers also presented their study last month at the American Association for the Study of Liver Diseases in Boston.

"Like other researchers, we previously used rat cells, too, but about a year and a half ago, when we submitted a paper to another journal, some of the reviewers began asking, 'what about human cells?'" says Dr. Pedro Baptista, lead author on the study. "That was the trigger for us to start working with them. One thing led to another, but working with human cells was really always our objective."

The purpose of the study, Baptista says, was to investigate the feasibility of generating a bioengineered human liver by re-cellularizing the liver bioscaffold with primary human fetal liver progenitor cells (hFLPCs) and endothelial cells (hECs). First, in a process called decellularization, the researchers treated animal livers with mild detergent to remove all cells, leaving the liver's collagen support structure intact. They then replaced the original cells with the fFLPCs and hECs, introducing them into the liver structure through a large vessel that feeds a system of smaller vessels in the liver. This network of vessels remains intact after the decellularization process. The liver was next placed in a small bioreactor developed by the researchers that provides a constant flow of nutrients and oxygen throughout the organ.

"The bioreactor allows us to seed and keep the structure going in vitro for a maximum of three weeks," Baptista says.

Immunohistochemistry showed progressive tissue formation, urea secretion, protacyclin secretion and widespread cell proliferation. Hepatic and endothelial tissue functions and cell proliferation were detected with 3D tissue progressive formation in vitro.

According to Baptista, this technology and process may provide a new approach for liver bioengineering, critical for drug discovery and treatment of terminal liver diseases.

"Providing livers to those who need transplants is of course our main goal," he says.

Bioengineered livers could also be useful for evaluating the safety of new drugs, Baptista adds.

"This would more closely mimic drug metabolism in the human liver, something that can be difficult to reproduce in animal models," he says.

Finally, Baptista says bioengineered livers could also have utility in oncology research.

"It might be quite interesting to use bioengineered livers to see how human metastases grow," he says.

Next, the Wake Forest team will test whether the livers will continue to function after being transplanted in an animal model. Still, Baptista stresses that this research is still in its early stages, many technical hurdles must be overcome before it can benefit patients. The engineered livers, which are about an inch in diameter and weigh about .20 ounces, would have to weigh about one pound to meet the minimum needs of the human body, said the scientists. Even at this larger size, the organs wouldn't be as large as human livers, but would likely provide enough function. Research has shown that human livers functioning at 30 percent of capacity are able to sustain the human body.

"Right now, we are not able to engineer enough cells to make a meaningful-size tissue or liver that could be transplanted," Baptista explains. "We are able to generate 100 to 300 million cells, but because we would need 100 billion cells for a human liver, we're still short, and it takes time to generate these cells. We don't have the enabling technologies to take human liver progenitor cells or liver stem cells and expend them from a few million to a few hundred billion cells. So since that technology is not here yet, one of our other projects is to put a lot of effort into easing this bottleneck that everyone faces."

Baptista's co-researchers were Dipen Vyas, B.Pharm., Zhan Wang and Anthony Atala, director of the institute.

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