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A Rudimentary Liver Is Grown from Stem Cells

A mixture of three cell types self-assembles into a liver bud that can be seen with the naked eye.

In work that will raise hope that organs could be repaired or even grown from scratch using a patient’s own tissue as the raw material, Japanese researchers have created functioning liver tissue from stem cells and successfully transplanted it into mice.

The researchers found that a mixture of human liver precursor cells and two other cell types can spontaneously form three-dimensional structures dubbed “liver buds.” In the mice, these liver buds formed functional connections with natural blood vessels and performed some liver-specific functions such as breaking down drugs in the bloodstream.

It’s possible the technique will work with other organ types, including the pancreas, kidney, or lungs, lead author Takanori Takebe, a scientist at Yokohama City University in Japan, said Tuesday at a press conference, aided by a translator. The study, published in Nature on Wednesday, is the first demonstration that a rudimentary human organ can be produced using induced pluripotent stem (iPS) cells, says Takebe.

These iPS cells are made by converting mature cells such as skin cells into a state from which they can develop into many other cell types (see “The Science of iPS Cells”). The discovery that mature cells can be reprogrammed to assume this state was the basis of the 2012 Nobel Prize in Physiology or Medicine.

The study provides a “precedent for thinking about making organs and reconstructing more complex three-dimensional structures or tissues,” says George Daley, director of the Stem Cell Transplantation program at Children’s Hospital in Boston. The researchers took a creative approach to building the proto-liver, says Daley, by commingling three different cell types: liver cell precursors derived from human iPS cells, blood vessel precursors called endothelial cells, and connective tissue precursor cells called mesenchymal stem cells. Both the blood vessel and connective tissue precursor cells were harvested from umbilical cords.

The findings from Takebe and his colleagues build upon existing work showing that culturing multiple cell types together can help researchers develop physiological three-dimensional tissues in the lab, says Yoon-Young Jang, director of the Stem Cell Biology Laboratory at Johns Hopkins University School of Medicine. Other groups have also shown that stem cells—when given the right chemical signals—can spontaneously develop into three-dimensional structures similar to natural tissues, such as the retina (see “Growing Eyeballs”).  

The methods used by the researchers in the new study also mimic some aspects of the natural embryonic development of the liver. Adhering to the principles of developmental biology in this way is a strategy that many in the field of regenerative medicine are taking, says Daley. “This study is a good example where generating a more ordered three-dimensional organoid is probably the route that most of us are going,” he says. “The ability of these organoids to mediate human liver-specific drug metabolism is a very impressive proof of principle for the utility of this approach.” 

To demonstrate the therapeutic potential of their technique, Takebe and colleagues transplanted a dozen liver buds into the abdomen of mice whose natural liver function was shut down with a drug. The transplants kept these mice alive for the month they were watched.

The liver buds did not achieve all the functions of a mature liver. For instance, they did not form a bile duct system. However, in ongoing research, the team has found that if the buds are transplanted into an existing liver, the body seems to make use of the existing bile system, Takebe said by e-mail.

Takebe said that one potential therapeutic use of the method could involve delivering microscopic liver buds to human patients through a large vein that connects to the liver to improve survival after liver failure. He said he was optimistic that as much as 30 percent of liver function could be restored through this method.

But Takebe estimated that such a treatment is at least 10 years away. In the meantime, the method must be improved so that the liver buds can be produced much more efficiently. “The problem is to create enough liver buds, in sufficient quantity, to make it a viable therapy,” he said.

“The potential of pluripotent stem cell therapy is great,” says Jang. But he cautions that “much more work needs to be done to demonstrate their true value in the clinic,” including long-term evaluation of their safety.

A more immediate use for iPS cells could be for screening candidate drugs. “Research using patient-relevant models of complex diseases such as liver cirrhosis and cancer would help in the discovery of better cellular and molecular targets for drug development,” Jang says.

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