May 4, 2001 NEW YORK, May 3 -- The ultimate adult stem cell appears to have been discovered--a cell in the bone marrow that can transform itself into almost any organ in the body, according to a new study by New York University School of Medicine, Yale University School of Medicine, and Johns Hopkins School of Medicine researchers.
"There is a cell in the bone marrow that can serve as the stem cell for most, if not all, of the organs in the body," says Neil Theise, M.D., Associate Professor of Pathology at NYU School of Medicine, who co-led the study. "This is an exciting study. Theoretically, any organ could be 2repaired using cells generated from this stem cell and bone-marrow-derived cells could be used to target gene therapy to a specific organ."
The new study is published in the May 4 issue of the journal Cell.
In the last three years, a growing number of studies have overturned long-held beliefs about stem cells in the bone marrow. It had been believed that in the adult, these bone marrow cells were committed only to making blood cells. But over the last three years, a growing number of studies have shown that these cells have surprising plasticity, and can transform themselves into mature cells of other organs such as skeletal muscle, bone, and brain. Dr. Theise and Dr. Diane Krause, Assistant Professor of Laboratory Medicine and Pathology at Yale University School of Medicine, were among the first to show that stem cells can become liver cells, as well, and the first to demonstrate this transformation in humans. Yet, until now, the stem cell from which these mature cells arose hadn't been identified.
In the new study, Dr. Saul Sharkis and colleagues at Johns Hopkins first purified stem cells in the bone marrow of male mice. Then they took just one of these cells and transplanted it into female mice that had their bone marrow destroyed by radiation. Eleven months later, the researchers found that the male cells had settled in the blood and bone marrow of the surviving female animals, using color dyes that light up the Y chromosome and other structures. The Y chromosome is only found in cells from males. When Drs. Theise and Krause looked, they found the male chromosome not only in the bone marrow and blood, as expected, but also in the tissue from the lung, esophagus, stomach, small and large intestines, liver, and skin.
"It had been thought that only embryonic stem cells had such wide-ranging potential," says Dr. Theise of NYU School of Medicine. "However, this study provides the strongest evidence yet that the adult body harbors stem cells that are as flexible as embryonic stem cells," he says.
"It's astounding that there are cells in our bone marrow that can become so many different cell types including blood, lung, GI tract and skin," says Dr. Krause of Yale University. "The challenges now are to elucidate how these changes occur and to harness these findings to develop therapies for many different human diseases."
Stem cells in the marrow may be recruited to a damaged organ where they will develop into the mature tissue of that organ in response to certain signals. However, Drs Theise and Krause speculate that any healthy adult cell with an intact genome can be reprogrammed to become a stem cell.
The study had two parts. In the first part, stem cells in the bone marrow were isolated and purified using a protocol developed by Dr. Sharkis. Bone marrow cells from male mice were spun in a centrifuge, partitioning cells according to their weight in a process called elutriation. Then the cells belonging to one of the partitions were exposed to a panel of antibodies that bind specifically to proteins in the cell membrane of mature red and white blood cells. Stem cells don't have these proteins in the membrane.
The cells that bound the antibodies were eliminated and the remaining cells were labeled with a fluorescent color dye that sits tightly between the fatty layers of the membrane of cells. These cells were then injected into female mice that had been irradiated, which destroys the cells in the bone marrow. After two days, the stem cells were recovered from the bone marrow of the female mice, and only those cells with the brightest color were used in the subsequent part of the study. The bright color indicated that the cells had not yet divided, assuring the researchers that these cells had the greatest transformative potential.
In the second part of the study, one of these bright-colored cells was plucked out of solution and transplanted into other female mice that had been irradiated. By killing the bone marrow, the stem cell would be forced to generate cells to repopulate the bone marrow of the recipient female mouse. Thirty female mice received the stem cell and five of the mice survived 11 months. Cells containing Y chromosomes were found in multiple organs in all five of these surviving mice.
This collaborative study was conducted by Neil Theise, Sonya Hwang, and Rebekah Gardner from NYU School of Medicine; Diane Krause and Octavian Henegariu from Yale; and Saul Sharkis, Sara Neutzel, and Michael Collector from Johns Hopkins. It was supported by grants from the National Institutes of Health, the American Liver Foundation, the Mary Lea Johnson Richards Research Institute, and the Robert Krieger Memorial Fund.
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