News Release

The bone marrow is the source of mature liver cells

Peer-Reviewed Publication

NYU Langone Health / NYU Grossman School of Medicine

New York, NY, June 26, 2000 -- In a finding that opens a new avenue to treating liver disease and blood clotting disorders, researchers have found that the bone marrow is the source of cells that are responsible for the liver's famous ability to regenerate itself. These cells, called stem cells, are recruited to the liver from the bone marrow and function as liver cells, according to a new study by New York University School of Medicine and Yale University School of Medicine scientists that proves for the first time that this process occurs in humans.

"We have proven that in humans there are stem cells for the liver in the bone marrow," says Neil Theise, M.D., Associate Professor of Pathology at New York University School of Medicine, the lead author of the new 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," he says.

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

The liver, too, supplies new recruits -- even if half of the organ is removed from the body, it regenerates with breathtaking speed -- but researchers have disagreed for many years about the origins of the liver's newfound cells. Some suspected there might be hepatic stem cells, but they lacked proof of their existence -- until now. (The ancient Greek myth of Prometheus is based on the liver's ability to regenerate. Each day a giant eagle eats the liver of Prometheus, who is bound by chains to a rock. And each day the liver subsequently grows back to its original size.)

"This is an exciting finding, and incredibly surprising because the bone marrow has never been considered as a source of liver cells," says Diane Krause, M.D., Ph.D., Assistant Professor of Laboratory Medicine at Yale University School of Medicine, an author of the new study. "Bone marrow is supposed to turn out blood cells. Liver is supposed to turn out liver cells," says Dr. Krause. "The goal is now to harness the potential of this finding into new avenues for therapeutics."

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

According to the American Liver Foundation, 26,000 Americans die each year from chronic liver diseases and cirrhosis.

In the new study, two women with leukemia, a blood-cell cancer, received bone marrow transplants from male donors as part of their therapy, and four men with severe liver disease received liver transplants from female donors. The researchers used the Y chromosome, which is found only in males, as a clever way to keep track of stem cells. The new study is published in the July issue of Hepatology, the official journal of the American Association for the Study of Liver Diseases.

The bone marrow contains a population of stem cells that are the progenitors of all the body's blood-forming cells. In leukemia and other cancers, a patient's own diseased bone marrow is removed prior to high-dose chemotherapy to kill existing cancer cells, and then the marrow from a healthy donor is infused into the patient.

Dr. Theise and co-workers subsequently examined liver tissue from the two leukemia patients. Using a microscope and a special staining procedure that gives the Y chromosome an immunofluorescent glow, they identified the male chromosome as a turquoise dot inside the nucleus of the women's liver cells. 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. 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, says Dr. Theise.

In the liver tissue from the four men who received transplants from females, the researchers found liver cells with Y chromosomes, indicating that these cells had come from the bone marrow. Women's cells contain two X chromosomes, so the transplanted liver cells contained only X chromsomes. Thus, the cells with Y chromosomes had to come from elsewhere in the body and the bone marrow seems the mostly likely place, says Dr. Theise.

In one of the men who received a transplant and who suffered from severe recurrence of hepatitis C, 40% of his liver cells contained Y chromosomes.

"Neil Theise is an innovative and creative investigator," says James Crawford, M.D., Chairman of Pathology at the University of Florida in Gainesville, who has collaborated previously with Dr. Theise and is familiar with the new study. "He has provided definitive evidence that in humans bone marrow cells can replace liver cells. His study is an important proof-of-concept needed to justify development of stem-cell therapy for liver disease."

Although it could be many years, if ever, before hepatic stem-cell transplants are attempted, 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 could possibly be used to generate replacements for organs in the body.

Over the last eight months, the journal Hepatology has published three of Dr. Theise's liver studies as cover articles, using pictures from each of the studies on its front covers. Dr. Crawford of the University of Florida said he doesn't know of another researcher who has received such attention in a high-level peer-reviewed medical journal.

In a study published in the December issue of Hepatology, Dr. Theise and co-workers described their surprising findings about a structure called the Canal of Hering (named in the 1800s after a German scientist), which acts as a recruitment station for stem cells. In the second study, published in January, Dr. Theise and co-workers showed that in mice bone marrow cells could become liver cells. That experiment was one of the foundations for the newly published study in humans.

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The new study was supported by grants from the Mary Lea Johnson Richards Research Foundation and the American Liver Foundation.


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