Tiny human livers grown from stem cells functional in mice

Stem cells generated from adult cells have been used to grow
tiny 'liver buds' which were then successfully transplanted into mice.

After transplantation the buds hooked up to the mice's blood
supply, matured and were ultimately able to break down drugs given to the mice -
a sign that they were working.

Experts were quick to applaud a development which, if
confirmed, would be an immense step forward in regenerative medicine. While
other body parts have already been grown and used clinically (see BioNews 485), solid organs like
the liver are the most difficult to generate from stem cells. At the same time,
there is a great need for therapies for such complex organ systems which do not rely entirely on organ donation.

While scientific commentators were unanimous in their praise
for the paper, most were cautious in anticipating any immediate benefits for
patients.

'Although the promise of an off-shelf-liver seems much
closer than one could hope even a year ago', Dr Dusko Ilic, reader
in stem cell science at King's College London said, 'the paper is only a
proof-of-concept. There is much unknown and it will take years before it could
be applied in regenerative medicine'.

The team behind the research, led by scientists at Yokohama
City University, were trying to mimic the conditions of early liver growth in
the embryo in their experiments. For this, they used human induced pluripotent stem (iPS) cells, originally generated from donated adult tissue, and coaxed them into
becoming liver cells.

These were then mixed with two other kinds of cells,
including from human umbilical cords. Professor Takanori Takebe told BBC News that he was 'completely gobsmacked' to see the cells 'self-organising to form a
three-dimensional liver bud - this is a rudimentary human liver'.

The buds developed their own blood vessels and on being injected
under the skin of lab mice connected to the mice's blood supply. Once
transplanted, the buds grew from their embryonic state into what appeared to be
adult liver tissue.

To check whether the liver buds worked, the scientists gave
two groups of transplant mice two different drugs. Blood tests showed breakdown
products, or metabolites, that could only be made by human liver and not mouse
liver.

In a further experiment, groups of normal and transplant mice were
given injections of diphtheria toxin in their tails. As expected, all the
normal, 'control' mice suffered liver failure and died within 10 days. Several
of the transplant mice, however, survived for over 40 days.

The scientists say that they would like to test liver bud injections in liver failure patients. In a change from previously envisaged
therapies, the liver buds would not replace the diseased liver but sit nearby
in the abdomen and support liver function.

But Professor Chris Mason, chair of regenerative medicine
bioprocessing at University College London, who was not involved in the study,
suggested that the liver buds' first application may be not in a clinical setting but
in drug testing.

The kinds of cells currently used in metabolism and toxicity
testing of new drugs, Professor Mason said, 'are only available in very limited
quantities, insufficient for routine early stage research'.

'However, from Takebe’s data, mice transplanted with human
iPS cell-liver buds might help developers predict drug metabolite profiles for
patients and thus enable early stage detection of unwanted side effects rather
than later during clinical trials, or worse, after the drug enters routine
clinical practice'.

The study was published in the journal Nature.