May 18, 1999 PITTSBURGH, May 13 -- Bone marrow-derived cells give rise to fully functional liver cells, researchers at the University of Pittsburgh Medical Center have found through a series of transplant experiments, yielding the first report that such stem cells provide a lineage for cells making up solid organs. Study results, published in the May 14 issue of Science, suggest that bone marrow-derived cells could eventually repair or replace injured or diseased livers, reducing the need for transplantation. At a theoretical level, the findings disrupt the scientific dogma that plastic fetal cells are needed to generate the differentiated cells of adult organs.
"This is a critical paper that bridges a gap in our understanding of how the liver repairs itself under certain physiological conditions," said Bryon Petersen, Ph.D., research associate in pathology at the University of Pittsburgh's School of Medicine and lead investigator on the study.
For more than 40 years, scientists have witnessed the appearance and proliferation of a distinctive group of cells, called oval cells, under special animal experimental conditions. Normally, healthy liver cells, or hepatocytes, regenerate an injured liver. But if hepatocyte division is suppressed experimentally and the liver is subsequently injured, oval cells appear on the scene. In this setting they proliferate, then transform into several types of functional liver cells, thus helping to repair the damaged organ. The origin of oval cells has remained controversial, although they are known to carry markers also seen on bone marrow cells.
"Our animal experiments using cross-sex bone marrow transplants clearly show that bone marrow-derived cells eventually become fully functional liver cells, quite probably through an intermediate oval cell," said Dr. Petersen. "The next step is finding the bone marrow stem cell giving rise to the oval cell or discovering the signal that the liver broadcasts to recruit such cells to the scene of injury."
Previous scientific reports have indicated that bone marrow cells give rise to two major tissue cell types: mesenchymal cells that develop into bone and muscle and endothelial cells that form the lining of blood vessels. This report is the first to indicate that bone marrow cells give rise to the third tissue cell type, epithelial cells, which can develop into solid organs.
Ultimately, cultures of the malleable bone marrow stem cells could aid patients with fulminant hepatic failure, in which the liver is unable to repair itself, according to Dr. Petersen. Such cultures could also provide important reservoirs of cells that could be used for gene therapy to repair defective livers or to protect against viral infection. These cells could be transplanted back into the patient without risk of rejection.
As part of their research, the investigators took female rats and irradiated them to deplete their bone marrow. These females then received bone marrow from male rats of the same species. After nearly two months, the male/female mixtures, or chimeras, were treated with a chemical that prevents healthy liver cells from reproducing. One week later, the scientists chemically injured the liver. Fifteen days after the injury, the scientists removed the livers and probed them for a marker found only on the male Y chromosome. They located oval cells and hepatocytes that carried the marker. This discovery suggests that stem cells traveled from the bone marrow to the liver in response to injury and differentiated into oval cells, which in turn became functional hepatocytes.
Dr. Petersen and his colleagues repeated this experiment using another type of marker. In addition, they tested the hypothesis of bone marrow-derived hepatocytes by transplanting whole livers from one rat species without a specific tissue marker (L21-6-negative), into another rat species with the marker (L21-6-positive). After suffering an experimental injury, the transplanted L21-6-negative livers showed evidence of repair with L21-6-positive cells, suggesting they came from a source outside the liver.
Collaborators on the study include Bill Bowen; Ken Patrene; Wendy Mars, Ph.D.; Art Sullivan, M.D.; Noriko Murase, M.D.; Sally Boggs, Ph.D.; Joel Greenberger, M.D.; and Judy Goff, Ph.D. All collaborators are with the University of Pittsburgh except Dr. Sullivan, who is with the department of hematology/oncology at McGill University in Quebec.
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