Tissue switching could lead to new diabetes
treatment.
A study hints that one
day portions of diabetics' livers might be converted into pancreas tissue in the
lab to restore healthy, insulin-producing cells, so that their bodies can store
nutrients properly.
UK researchers have
made tadpoles grow pancreas tissue from their liver cells, and turned human
liver cells into pancreas cells in the lab1.
"This is just the
first step," says study leader Marko Horb of the University of Bath. "The next
is to show that these cells are functional. Then we have to show that we can
cure a mouse model of diabetes, and finally test how it would work in humans."
There are 150 million diabetics worldwide.
During embryo
development, liver and pancreas cells grow from similar, adjacent tissues. In
mice and humans the gene Pdx1 is essential for a pancreas to form. It
codes for a protein that directs others in the cell - in a sense it gives the
cell its identity.
"We thought if we can
find the master-switch gene for pancreas and somehow deliver it to liver cells,
we could transdifferentiate liver into pancreas," Horb explains. So they put
activated Pdx1 into frog embryos. Liver cells that had the gene converted
into pancreas. In some tadpoles the whole liver was converted; in others just a
few cells switched.
The same thing
happened to adult human liver cells in a dish. The transdifferentiated tissue
appears to remain stable, at least for as long as the researchers tested - up to
two weeks in the tadpoles and seven days in the human cells.
The switched tissue
secretes the main products of the pancreas: insulin, glucagon and amylase. The
group now plans to test whether or not it produces these properly in response to
appropriate signals, such as glucose in the case of insulin.
Other researchers are
impressed but cautious. "We worry that this funny gene construct could be
spontaneously activated at a later stage - it might have cancer-causing
potential," says Chris Wright who studies pancreas development at Vanderbilt
University Medical Center in Nashville, Tennessee. Controlling the amount of
conversion to insulin-producing cells is also crucial, he adds.
But Wright praises the
cleverness of the team's technique. They strung together several pieces of DNA
along with Pdx1 to trick the liver cells into taking on a new identity.
They put a liver-specific driver on Pdx1, attached a universal activator
from the herpes simplex virus, and hooked on the gene for green fluorescent
protein to mark out cells that had taken up the string.
"The idea of making a
designer transcription factor to coax or convert particular stem cells into
organs would be remarkable," says Wright. The viral universal activator could
turn into a "magic shortcut" for embryonic-stem-cell researchers.
And, points out Horb,
the liver-specific driver acts as an automatic shut-off valve once the tissue
switches to pancreas - in theory, making reactivation of the gene impossible.
Horb, M.E., Shen, C.-N., Tosh, D. & Slack, J.M.W. Experimental conversion of liver to pancreas.
Source: Diabetes In Control Dot
Com: Current Biology,
13,
105
- 115,
(2003).
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