Do liver stem cells come from bone marrow?

The gods of Greek mythology knew a thing or two about anatomy. To punish Prometheus for giving fire to humans, Zeus had him chained to a rocky mountainside where each day an eagle would devour his liver. Overnight, it would grow back, prolonging Prometheus' suffering. The legend picked on the right organ: Unlike many body parts, liver tissue does regenerate.

The biological mechanisms underlying this regeneration are far from clear, although studies of animals indicate that liver damage makes the body produce chemicals that spur liver cells to multiply. Scientists now report another source of new liver cells. Human stem cells lurking in adult bone marrow apparently can become liver cells during a crisis.

When liver damage from injury or disease outpaces the rate of repair, the patient becomes a candidate for a liver transplant. The discovery that liver-cell reinforcements reside in the marrow opens up the possibility that such cells might be cultured to aid in rebuilding a damaged liver without the need for a transplant, says study coauthor Neil D. Theise, a pathologist at New York University School of Medicine.

Animal studies had suggested that cells from bone marrow could develop into liver cells. To test this idea, Theise and his colleagues used a natural biological marker, the Y chromosome, which exists only in cells of males. They studied two women with leukemia who had received bone-marrow transplants from men. After 13 months, samples of liver tissue taken from one woman revealed that more than 10 percent of her liver cells contained a Y chromosome. Nearly 5 months after the other woman's transplant, a Y chromosome showed up in 5 percent of her liver cells, the researchers report in the July HEPATOLOGY.

These Y-carrying cells must have either come from the bone marrow or passed through it on their way to the liver, Theise says.

The researchers also examined four men who had received liver transplants from female donors. These livers were initially free of Y chromosomes. At various points between 1 month and 2 years after transplant, 16 to 40 percent of liver cells in these men contained a Y chromosome.

The male patient with the highest number of liver cells bearing the Y chromosome also had the most dire disease--recurrent hepatitis C. The findings suggest that severe injury to the liver, even by a virus, spawns extra liver-cell production from distant stem cells, Theise says. In such cases, he notes, "it would seem that the bone-marrow part of the process predominates" over cell regeneration in the liver itself.

The findings don't indicate whether the men's new liver cells came directly from the marrow, says study coauthor Diane S. Krause, a biologist at Yale University School of Medicine. "We only know they are from the blood of these men. But it's very likely that if they were in the blood they were in the bone marrow," she says.

The study represents "very interesting work," says Lawrence S.B. Goldstein, a cell biologist at the University of California, San Diego, in La Jolla. If this can be reproduced, he says, it will be consistent with an emerging line of evidence showing that bone marrow and other adult tissues harbor cells that have the potential to develop into different tissues.

James M. Crawford, a pathologist at the University of Florida College of Medicine in Gainesville, says, "This paper will stimulate an enormous effort to examine human tissues for evidence of tissue replenishment" from remote sites.

Cells from the liver don't grow well in culture, making them difficult to mass-produce. However, stem cells from animals' bone marrow grow readily in laboratory dishes. Scientists are working to identify which cells in human bone marrow are capable of becoming liver cells. "Only then can we learn the potential of this finding for therapeutic use," Krause says.