June 29, 2000 New Haven, Conn. -- Mature liver cells in humans are generated from bone marrow-derived stem cells, a Yale-NYU team 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," said Diane Krause, M.D., senior author of the study, and assistant professor in the Department of Laboratory Medicine and Pathology at Yale School of Medicine. "The long-held belief has been that bone marrow is supposed to produce blood cells and 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 female donors. Bone marrowderived cells were identified by the presence of the Y chromosome, which is found only in males.
"We have proven that in humans there are stem cells for the liver in the bone marrow," said Neil Theise, M.D., 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."
In this groundbreaking study, researchers show-using a special stain that makes the Y chromosome glow under the fluorescent microscope-that there were liver cells that had the Y chromosome in the otherwise female livers of the female leukemia patients. The only possible source of these cells was the donated bone marrow. In one patient, 17 percent of her liver cells-almost one in five-carried the Y chromosome, some 13 months after she received the transplant. Theise said 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 liver from female donors, the researchers again found cells that had a Y chromosome, 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.
It has been known for some time that there are cells within the liver that can regenerate lost liver tissue, but researchers have disagreed 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. 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.
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 on the study included Manjunath Nimmakayalu, Rebecca Gardner, Peter Illei, M.D., Glyn Morgan, M.D., Lewis Teperman, M.D., and Octavian Henegariu, M.D.
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