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Liver Cells Converted to Pancreas Beta Cells

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. Current Biology, 13, 105 - 115, (2003).

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