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article imageJapanese scientists use stem cells to grow human liver in mouse

By JohnThomas Didymus     Jul 4, 2013 in Science
Japanese scientists have for the first time grown a functional human liver from stem cells derived from skin and blood tissues. They used stem cells to grow "liver buds" which grew into a functional human liver after they were injected into mice.
The scientist were able to coax stem cells in the laboratory to grow and form three-dimensional structures they called "liver buds," which have the potential to grow into full organs.
They then transplanted them into mice where they matured and formed vessels connecting to the host's blood vessels.
According to Takanori Takebe, a stem cell biologist at the Yokohama City University Graduate School of Medicine in Japan, who led the study, this is the first time that researchers have created a complex human organ using reprogrammed induced pluripotent stem cells (iPS) derived from mature skin cells.
Scientists use two main types of stem cells in research : Reprogrammed "induced pluripotent stem cells," (iPS) usually derived from skin and blood tissues, and embryonic stem cells harvested from embryos.
The team used iPS cells to make three different types of cells that grow together into a complete human liver during normal embryonic development: hepatic endoderm cells, mesenchymal stem cells and endothelial cells.
They then demonstrated a new method that would make it possible to treat liver failure. They injected the tiny replacement buds into mice where the cells self-organized and grew into functional organs.
The "liver buds" were able to restore liver function and stave off death in mice suffering liver failure.
Nature reports that Takebe and his colleagues transplanted the buds surgically at sites in the cranium and abdomen of the mice. The researchers hope that in future trials they will be able to create liver buds small enough to be delivered intravenously in mice and finally in humans.
In a paper published in the journal Nature titled "Vascularized and functional human liver from an iPSC-derived organ bud transplant," Takebe and his colleagues write:
Here we show the generation of vascularized and functional human liver from human iPSCs by transplantation of liver buds created in vitro (iPSC-LBs). Specified hepatic cells self-organized into three-dimensional iPSC-LBs by recapitulating organogenetic interactions between endothelial and mesenchymal cells5... Human vasculatures in iPSC-LB transplants became functional by connecting to the host vessels within 48 hours. The formation of functional vasculatures stimulated the maturation of iPSC-LBs into tissue resembling the adult liver... To our knowledge, this is the first report demonstrating the generation of a functional human organ from pluripotent stem cells.
The liver buds showed potentials for full functional capacity by quickly linking with other blood vessels in the host and growing into functional tissues capable of secreting liver-specific proteins and producing human-specific metabolites.
The team said that soon it would be possible to treat damaged liver tissues by injecting thousands of microscopic "liver buds" into the blood stream of patients. The liver buds would incorporate themselves into the damaged liver and restore liver function.
Reuters reports the researchers said that although it might take several years of research and testing before lab-grown livers could be available for human patients, they are confident they now have proof that the concept is feasible and that it could be applied to other organ-growing research work.
According to Nature, Valerie Gouon-Evans, an expert in liver development and regeneration at the Mount Sinai Hospital in New York, who was not involved in the study, said: “This is a very novel thing." She said that because the liver buds are able to link up with the host's circulatory system they have the potential to grow into a new whole organ.
She noted, however, that animals who have received such transplant will need to be observed closely for several months to see whether the cells degenerate or form tumors.
Reuters reports that Dusko Illic, a stem cell expert at King's College London, said: "The promise of an off-the-shelf liver seems much closer than one could hope even a year ago."
He said that while the new method was promising and represents a major breakthrough "there is much unknown and it will take years before it could be applied in regenerative medicine."
The significance of the research arises from the scarcity of human livers for transplant surgery. There is a global critical shortage of donor organs for patients in need of organ transplant surgery.
In 2011, 5805 adult liver transplants were done in the US alone. About 2,938 patients died while waiting for new livers, Nature reports.
The breakthrough is part of an ongoing international research effort to make use of the ability of stem cells to differentiate into different types of cells, to treat organ failure in humans and create organs for transplant surgery.
According to Nature, the main thrust of research has involved two major different approaches: The first, used mostly for simple hollow organs such as the bladder, involves culturing entire organs in the laboratory using a "scaffold" structure and then transplanting them into patients. The other approach on which the current work is based involves creating pure cultures of cells in the laboratory that can be infused into the patients in the hope that they would be able to proliferate after infusion.
In April, a team of scientists used the "scaffold" approach to create a kidney in a lab that was able to function like a natural one. In May last year, British researchers said they have grown heart tissues from skin cells, Reuters reports.
According to Nature, Takebe said that the project took off after an unexpected observation while he was researching ways of making vascularized liver tissues. While attempting to culture different cell types together, he observed to his surprise that they showed the ability to self-organize into three dimensional structures.
Takebe believes that the approach could work for other organs such as lung, pancreas and kidney. According to Reuters, he told a teleconference that he found the study results so encouraging that he plans to do further research on the applicability of the concept to growing other vital organs.
Nature reports that researchers have also observed self-organizing capabilities in other organ systems such as certain types of optic tissues in the early developmental stages of the eye.
According to Reuters, Malcolm Allison, an expert at Queen Mary University of London, said the study offered "the distinct possibility of being able to create mini livers from the skin cells of a patient dying of liver failure" and transplant them to restore the organ's function.
Matthew Smalley, of Cardiff University's European Cancer Stem Cell Research Institute, said the prospects were exciting: "(This) study holds out real promise for a viable alternative approach to human organ transplants."
Chris Mason, an expert at the University College London, said the greatest impact of the study might be in their use in drug development research. He said: "Presently to study the metabolism and toxicology of potential new drugs, human cadaveric liver cells are used. Unfortunately these are only available in very limited quantities."
Nature reports that Kenneth Zaret, an expert in regenerative medicine and liver development at the University of Pennsylvania in Philadelphia, said: "It’s a great day for developmental biology. By reconstituting cell interactions that we know are important for natural liver progression, they get what appears to be robust, mature tissue."
According to an Zaret, the study could lead to a new approach to growing organs which exploits the ability of the cells to self-organize. He said: "Basically, put the cells in a room together and let them talk to each other and make the organ.”
More about Human liver, Stem cells, induced pluripotent stem cells, Takanori Takebe
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