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New Lease on Livers

Animal experiments suggest that bone marrow might be used to rebuild damaged organs
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Image: UNIVERISTY OF PITTSBURGH MEDICAL CENTER

SETTING THE STAGE. Researchers first irradiate female rats to rid them of their own bone marrow (left) and give them transplants from males of the same species (center). Then they suppress the ability of hematocytes in the chimera from reproducing and repairing any liver damage (right).

Bone marrow--long known for its ability to generate bone, muscle and blood vessel linings--has a new trick: researchers at the University of Pittsburgh Medical Center report in the May 14 issue of Science that it can spawn liver cells as well. Not only does this discovery shatter the belief that fetal cells alone can create differentiated cells like those found in adult organs, it also explains why the liver sometimes repairs itself and promises alternatives for when it doesn't.

In fact, the liver has remarkable powers of regeneration. Liver cells called hepatocytes readily divide and replace damaged tissue. If they are too few in number or otherwise suppressed, they can be transplanted--but "even among patients with fulminant hepatic failure, who you would expect to die in a week, 20 percent survive without any intervention," says Bryon Petersen, the lead investigator from the Pittsburgh team. In these cases, so-called oval cells step in.

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Image: UNIVERISTY OF PITTSBURGH MEDICAL CENTER

REGENERATION. The team injured the chimeras' livers (top), waited for them to regenerate (middle) and then harvested them (bottom). Upon examination, they found that the new liver tissue bore markers found only on the Y chromosome, proving that bone marrow from the male rats had made the repairs.

Petersen's group set out to establish that the miracle-working oval cells--whose origin has long been controversial--were derived from bone marrow stem cells, an idea they began testing in 1995. First they irradiated female rats to destroy their bone marrow and then gave them transplants from males of the same species, creating chimeras.

Nearly two months later, they treated the chimeras with 2-AAF, a substance that prevents hepatocytes from reproducing and thus repairing injured tissue. Within a week, they injured the rats' livers using yet another chemical. And after two weeks, they harvested the livers and looked for a marker found only on the Y chromosome and so could only be derived from the male rats' marrow.

What they discovered was that the livers contained both oval cells and healthy hepatocytes bearing the marker. "These experiments clearly show that bone marrow-derived cells eventually become fully functional liver cells, quite probably through an intermediate oval cell," Petersen says.

Additional evidence comes from a second set of tests in which the group tranplanted whole livers from one rat species into another. Liver cells from the recipient rats bore a marker called L21-6, whereas those from the donors did not. The group found that when they injured the rats' livers and suppressed hepatocyte division, new tissue arose bearing L21-6, suggesting that cells from outside the organ had made the fixes.

"If we are able to exploit this model," Petersen notes, "we might be able to get these cells from a person's bone marrow and make 60 to 80 percent of a liver." Patients facing total hepatic failure could then avoid a transplant and the risks associated with immunosuppression. Because the cultures would be from their own body, the possibility of rejection would be eliminated. And tissue cultures aside, the bone marrow cells might also be used in gene therapies or to protect livers against such viral infections as hepatitis C.

Petersen sees an even loftier therapeutic goal: If they could discover the signal that damaged livers sometimes send out to recruit oval cells, a shot of it might suffice in even the most serious cases. At this point, though, any help is welcome for the hundreds of people who annually undergo transplants--and more so for those who aren't lucky enough to make the list.

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