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 patients own tissue as the raw material, Japanese researchers have created functioning liver tissue from stem cells and successfully transplanted them 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 perform some liver-specific functions such as breaking down drugs in the bloodstream.

Its 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 this powerful state thats useful for experiments 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 Childrens Hospital in Boston. The researchers took a creative approach to building the proto-liver, says Daley, by co-mingling 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 co-culturing multiple cell types 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 cellswhen given the right chemical signalscan 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 the liver bud method, Takebe and colleagues transplanted a dozen liver buds into the abdomen of mice whose natural liver function was shut down with a drug. The liver bud 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, the buds did not form a bile duct system. However, in ongoing research, the team has found that by transplanting the buds into an existing liver, the body seems to make use of the existing bile system, Takebe said by email.

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A Rudimentary Liver Is Grown from Stem Cells