First Organ Grown From Stem Cells Alone: Report

Researchers say their advance, with livers for mice, may one day increase availability of human transplants

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By Brenda Goodman

HealthDay Reporter

WEDNESDAY, July 3 (HealthDay News) -- Japanese scientists report they've turned a cocktail of stem cells into the world's first functioning livers.

The tiny livers were created in the lab and transplanted into mice, where they grew and began to perform the same functions as human-sized livers, including metabolizing drugs and making liver-specific proteins.

Though very basic -- the experimental livers don't have all the features of full-grown organs -- it's believed to be the first time scientists have grown a three-dimensional organ in the lab using only cells.

Previously, scientists have made solid organs using stem cells that are seeded onto some kind of scaffold, either a donor organ that's been washed of all its original cells or some kind of artificial material.

But one expert said this latest approach takes the concept one step further.

"This is a different strategy to create tissues and organs," said Dr. Anthony Atala, director of the Wake Forest Institute of Regenerative Medicine, in Winston-Salem, N.C.

"The work is very important because it allows you to study how organs are created and how they give rise to more functional complex systems," Atala said. "This is a nice advance."

With further study, researchers think their technique could one day solve the critical shortage of human organs for transplantation.

"We are now assessing the applicability to other organs such as the pancreas and kidneys because they have a similar kind of developmental course as the liver. So far, we've had fascinating results," Takanori Takebe, a professor of regenerative medicine at the Yokohama City University Graduate School of Medicine, said at a press briefing.

Takebe added that he thought it would take at least 10 years before an organ grown this way could be transplanted into a person.

For the experiments, described online July 3 in the journal Nature, researchers mixed three different kinds of stem cells that each turn into a different kind of tissue.

Pluripotent stem cells -- which have the ability to differentiate into nearly any type of cell in the body -- were induced to become liver endoderm, the germ layer that creates the spongy bulk of liver tissue. Those cells were mixed with mesenchymal stem cells, which produce connective tissue, and a population of stem cells derived from human umbilical cord blood that grow into the tissue that lines blood vessels.

Mixing cell types was important because it mimicked the same process that happens during fetal development. The different cell types use chemical signals to talk to each other, orchestrating the process of organ formation.

"There are no other groups that [I am] aware of that have tried the method described in the paper," Takebe said through a translator.

This is something which other people have kind of overlooked in their desire to develop and grow pure cell lines, that is the mixing of stem cells plus other factors that would be required for the formation of an organ, Takebe said.

After four to six days of growth in a petri dish, the liver buds, as scientists called them, were transplanted into mice where they quickly formed new blood vessels that looked like the networks of arteries and veins in adult livers. The experimental livers continued to grow for about two months in their mouse hosts.

The vessel growth was an important advance, according to one expert.

"That is a critical step forward, being able to hook it up in the blood vessels so beautifully," said Dr. Mark Donowitz, the Leboff Professor of Medicine at Johns Hopkins University in Baltimore.

Researchers tested them at various stages of development to make sure they were forming normally. After 10 days, the livers began producing human liver proteins.

The scientists even challenged the livers with medications like the painkiller ketoprofen, a drug that humans and mice metabolize differently. The urine of mice with transplanted liver buds showed byproducts of human drug metabolism, another sign that livers maintained their human origins.

In a final experiment, scientists transplanted the new liver buds into mice with liver failure. The transplanted buds improved their survival, when compared to mice in liver failure that were subjected to sham surgeries.

Despite all these promising signs, researchers said they would continue to be on the lookout for two risks in future experiments -- cancer and transplant rejection.

In addition to developing into new kinds of organs and tissues, stem cells can also turn into tumors, a problem that's a constant worry in the field of regenerative medicine.

And because the organs were grown from cell lines taken from three different humans, they might be rejected by the immune system of the eventual host. For that reason, researchers think people who receive these kinds of lab-grown organs may still need anti-rejection drugs.

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SOURCES: Anthony Atala, M.D., director, Wake Forest Institute of Regenerative Medicine, Winston-Salem, N.C.; Mark Donowitz, M.D., Leboff Professor of Medicine, Johns Hopkins University, Baltimore; press briefing with: Takanori Takebe, professor, regenerative medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan; July 3, 2013, Nature, online
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