Researchers in Japan have used human stem cells to create tiny human livers like those that arise early in fetal life. When the scientists transplanted the rudimentary livers into mice, the little organs grew, made human liver proteins and metabolized drugs as human livers do.
They and others caution that these are early days and this is still very much basic research. The liver buds, as they are called, did not turn into complete livers, and the method would have to be scaled up enormously to make enough replacement liver buds to treat a patient. Even then, the investigators say, they expect to replace only 30 percent of a patient’s liver. What they are making is more like a patch than a full liver.
The study was published Wednesday in the journal Nature.
Although human studies are years away, said Dr. Leonard Zon, director of the stem-cell research program at Boston Children’s Hospital, this, to his knowledge, is the first time anyone has used human stem cells, created from human skin cells, to make a functioning solid organ, like a liver, as opposed to bone marrow, a jellylike organ.
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Human stem cells — harvested first from embryos and now, more often, from skin cells — can turn into any type of human cell, and so it seemed logical to simply turn them into liver cells, for example, and add them to livers to fill in dead or damaged areas.
The investigators, led by Dr. Takanori Takebe of the Yokohama City University Graduate School of Medicine, began with human skin cells, turning them into stem cells. By adding various stimulators and drivers of cell growth, they then turned the stem cells into human liver cells and began trying to make replacement livers.
When they grew the human liver cells in petri dishes along with blood-vessel cells from human umbilical cords and human connective tissue, that mix of cells, to their surprise, spontaneously assembled itself into three-dimensional liver buds, resembling the liver at about five or six weeks of gestation in humans.
Then the researchers transplanted the liver buds into mice, putting them in two places: on the brain and into the abdomen. The investigators covered the hole in each animal’s skull with transparent plastic, giving them a direct view of the developing liver buds. The buds grew and developed blood supplies, attaching themselves to the blood vessels of the mice.
The abdominal site allowed them to put more buds in — 12 buds in each of two places in the abdomen, compared with one bud in the brain — which let the investigators ask if the liver buds were functioning like human livers.
They were. They made human liver proteins and also metabolized drugs that human livers — but not mouse livers — metabolize.
Even if the liver buds never fulfill their clinical promise, they still could be enormously important for pharmaceutical research, Zon said. Drugs must be tested to see if they damage the liver, a major site of drug toxicity. Companies do this with liver cells taken from cadavers and grown in petri dishes. But the liver buds could be a big improvement and offer a large supply of rudimentary livers for testing.