Yale Bulletin and Calendar

July 21, 2000

Volume 28, Number 35

Discovery may yield new therapies for liver disease

Mature liver cells in humans are generated from bone marrow-derived stem cells, a team of Yale and New York University researchers has discovered, paving the way for improved treatment of liver damage and disease.

"This is an exciting finding, and incredibly surprising because the bone marrow has never been considered a source of liver cells," says Dr. Diane Krause, assistant professor in the Department of Laboratory Medicine and Pathology at the School of Medicine. "The long-held belief is that bone marrow is supposed to produce blood cells. Liver is supposed to produce liver cells. Now that we know differently, the goal is to harness the potential of this finding into new avenues for therapeutics."

The study, published in the July issue of Hepatology, analyzed liver samples from female leukemia patients who had undergone bone marrow transplantation from a male donor, and from male liver disease patients who had received a liver transplant from a female donor. Bone marrow-derived cells were identified by the presence of a Y-chromosome found only in males.

"We have proven that in humans there are stem cells for the liver in the bone marrow," says Dr. Neil Theise, associate professor of pathology at New York University School of Medicine and lead author of the study. "These cells potentially could be used as a source of cells for liver transplants, as a pool of cells for the development of an artificial liver and in gene therapy to treat many liver diseases."

Stem cells were long thought to be limited to organs that supply new cells throughout life, such as blood cells from bone marrow and skin cells from skin. Cells from bone marrow, for example, couldn't become anything but blood cells.

In the livers of the female leukemia patients, the researchers demonstrated -- using a microscope and a special staining procedure that gives the Y chromosome an immunofluorescent glow -- that there were liver cells that had the Y chromosome. The only possible source of these cells was the donated bone marrow. In one patient, 17% of her liver cells -- almost one in five -- carried the Y chromosome, some 13 months after she received the transplant. Theise says the finding suggests that the liver normally adds new cells over time because the woman's liver was not damaged by the bone marrow transplant.

In the liver tissue from the men who received livers from female donors, the researchers again found cells with Y chromosomes, indicating that these liver cells had come from the men's own blood cells. Women's cells contain two X chromosomes and men's cells contain one X and one Y. Although the transplanted liver cells contain only X chromosomes, one man who received a transplant and who suffered from severe recurrence of hepatitis C, had Y chromosomes in 40 percent of his liver cells.

The liver is the body's workhorse for many metabolic functions and it also supplies blood-clotting factors. It is theoretically possible that healthy genes could be inserted into hepatic stem cells from bone marrow, and these new cells would correct metabolic and blood-clotting abnormalities.

The liver also supplies new cells. Even if half of the organ is removed from the body, it regenerates with great speed, but researchers have disagreed for many years about the origins of the liver's newfound cells. Some suspected these cells might be linked to hepatic stem cells, but proof of their existence was lacking until now.

Bone marrow stem-cell research is evolving rapidly, the researchers note. In the last two years, a steady procession of studies has overturned long-held beliefs about stem cells. Now it is known that these cells are capable of transforming themselves into many types of tissue, including brain and muscle tissue. Like pieces of clay that can be sculpted into any design, they may one day be used to generate replacements for organs in the body, scientists say.

Krause and Theise also collaborated on a study published in January, in which they showed that bone marrow cells could become liver cells in mice. That experiment was one of the foundations for this current study in humans.

This new study was supported by grants from the Mary Lea Johnson Richards Research Foundation and the American Liver Foundation. In addition to Krause and Theise, other researchers involved in the study included Manjunath Nimmakayalu and Rebecca Gardner, and Drs. Peter Illei, Glyn Morgan, Lewis Teperman and Octavian Henegariu.

-- By Karen Peart

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