Again we have critical progress that promises
to short circuit organ restoration. The
majority of need can be solved by tissue replacement and this work paves the
way for livers and most organs.
We have an expensive standing army of the
tissue deficient out there whose elimination would represent both a medical and
economic revolution. That is what is
clearly in sight and it is already a priority target even while everyone tries
to keep our hopes under control.
It really is the most visible reward out there
for our decades of intensive medical research.
Miniature human liver grown in mice
Cells self-organize and grow into functional organs after
transplantation.
03 July 2013
Transplanting tiny 'liver buds' constructed from human stem cells
restores liver function in mice, researchers have found. Although preliminary,
the results offer a potential path towards developing treatments for the
thousands of patients awaiting liver transplants every year.
The liver buds, approximately 4 mm across, staved off death in mice
with liver failure, the researchers report this week in Nature1.
The transplanted structures also took on a range of liver functions —
secreting liver-specific proteins and producing human-specific metabolites. But
perhaps most notably, these buds quickly hooked up with nearby blood vessels
and continued to grow after transplantation.
The results are preliminary but promising, says Valerie Gouon-Evans,
who studies liver development and regeneration at Mount Sinai Hospital in New
York. “This is a very novel thing,” she says. Because the liver buds are
supported by the host’s blood system, transplanted cells can continue to
proliferate and perform liver functions.
However, she says, the transplanted animals need to be observed for
several more months to see whether the cells begin to degenerate or form
tumours.
There is a dire scarcity of human livers for transplant. In 2011, 5,805
adult liver transplants were done in the United States. That same year, 2,938
people died waiting for new livers or became too sick to remain on waiting
lists.
However, attempts to create complex organs in the laboratory have been
challenging. Takanori Takebe, a stem-cell biologist at Yokohama City University
in Japan who co-led the study, believes this is the first time that people have
made a solid organ using induced pluripotent stem cells, which are created by
reprogramming mature skin cells to an embryo-like state.
Testing whether liver buds could help sick patients is years away, says
Takebe. Apart from the need for longer-term experiments in animals, it is not
yet possible to make liver buds in quantities sufficient for human
transplantation.
In the current work, Takebe transplanted buds surgically at sites in
the cranium or the abdomen. In future work, Takebe hopes to create liver buds
small enough to be delivered intravenously in mice and, eventually, in humans.
He also hopes to transplant the buds to the liver itself, where he hopes they
will form bile ducts, which are important for proper digestion and were not
observed in the latest study.
Self-organizing structures
The researchers make the liver buds from three types of human cells.
First, they coax induced pluripotent stem cells into a cell type that expresses
liver genes. Then they add endothelial cells (which line blood vessels) from
umbilical cord blood, and mesenchymal stem cells, which can make bone,
cartilage and fat. These cell types also come together as the liver begins to
form in the developing embryo.
“It’s a great day for developmental biology,” says Kenneth Zaret, who
studies regenerative medicine and liver development at the University of
Pennsylvania in Philadelphia. “By reconstituting cell interactions that we know
are important for natural liver progression, they get what appears to be
robust, mature tissue.”
The project began with an unexpected phenomenon, says Takebe. Hoping to
find ways of to make vascularized liver tissues, he tried culturing multiple
cell types together and noticed that they began to self-organize into
three-dimensional structures. From there, the process for making liver buds
took hundreds of trials to tweak parameters such as the maturity and ratios of
cells.
Other organs
This strategy takes a middle path between two common strategies in
regenerative medicine. For simple, hollow organs such as the bladder and
trachea, researchers seed scaffolds with living cells and then transplant the
entire organ into patients. Researchers have also worked to create pure
cultures of functional cells in the laboratory, hoping that cells could be
infused into patients, where they would establish themselves. But even if the
cells work perfectly in the laboratory, says Gouon-Evans, the process of
harvesting cells can damage them and destroy their function.
Zaret thinks that the liver buds work might encourage an
intermediate approach. “Basically, put the cells in a room together and let
them talk to each other and make the organ.”
Self-organizing structures from stem cells have also been observed for
other organ systems, such as the optic cup, an early structure in eye
development2.
And 'mini-guts' have been grown in culture from single human stem cells3.
Takebe believes that the self-organizing approach might also be
applicable to other organs, such as lung, pancreas and kidney.
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