In mouse-tissue cultures, scientists found that stem cells, in the presence of cells from damaged liver tissue, developed into liver cells in as little as seven hours. They also observed that stem cells transplanted into mice with liver injuries helped restore liver function within two to seven days. The work was published in the June 1 issue of the journal Nature Cell Biology.
Bone marrow stem cells, also known as hematopoietic stem cells, have the ability to differentiate and develop into all other blood and marrow cells. There has been debate among the scientific community over whether these cells also can differentiate into other tissue types such as the liver, says Saul J. Sharkis, Ph.D., senior author of the study and a professor of oncology at the Johns Hopkins Kimmel Cancer Center. Some studies suggest that the bone marrow cells fuse with other types of cells, taking on those cells' properties. But in this study, the researchers found, through highly thorough analysis with a microscope and other tests, that the cells did not fuse, suggesting that "microenvironmental" cues from existing liver cells caused them to convert.
"The hematopoietic stem cells were capable of taking on many characteristics of liver cell types, including specific gene and/or protein expression as well as typical function," Sharkis says. "These events occurred rapidly after injury exposure and restored liver abnormalities, indicating that the cells converted."
This type of stem cell technique could eventually be used to treat chronic diseases such as diabetes, cirrhosis of the liver, heart disease and cancer, he says. He cautions that many more studies must be completed before the stem cell therapy can be tested in humans.
For the study, Sharkis and colleagues cultured bone marrow stem cells together with either normal or damaged liver tissue in tissue culture dishes. Liver tissue was taken from mice that had been exposed to liver-damaging drugs. The two cell types were separated by a thin, permeable wall. Researchers performed several tests looking for expression of liver proteins.
In as little as seven or eight hours after culture with the injured liver tissue, some of the stem cells expressed the typical proteins present in liver cells cytokeratin 18 or albumin. Two days after culture, nearly 3 percent of all stem cells expressed these proteins. The researchers also observed the expression of many other proteins and products normally manufactured by liver cells in their earliest stages -- all detected within eight to 48 hours of culture.
The team then used a sensitive microscope test to examine the sex chromosomes of the cells, as the stem cells were taken from male mice and the liver tissue was taken from female mice. They identified some stem cells of male donor origin with four sex chromosomes typical of liver cells but not stem cells, indicating that the stem cells themselves physically had started to change and did not fuse with the liver cells.
Finally, the team transplanted the stem cells into injured livers in female mice and studied the amount of conversion at two and seven days following the transplant. More converted cells were observed at seven days versus two days, suggesting that the cells remained viable and continued dividing or converting. The liver functions of mice receiving the stem cells recovered as early as two days after transplant.
Sharkis' continuing studies will try to identify the environmental cues responsible for cells' conversion, and examine the ability of stem cells to repair other organs.
The study was funded by the National Heart, Lung and Blood Institute, the Ludwig Foundation and Hopkins' Institute for Cellular Engineering. Co-authors were Yoon-Young Jang M.D., Ph.D.; Michael I. Collector; Stephen B. Baylin, M.D.; and Anna Mae Diehl, M.D.
Jang, Yoon-Young et al, "Hematopoietic Stem Cells Convert Into Liver Cells Within Days Without Fusion," Nature Cell Biology, June 1, 2004.
Johns Hopkins Kimmel Cancer Center
Nature Cell Biology