Aug. 13, 2004 A single type of primitive stem cell transplanted from donor mice gave rise to both blood-forming and bone-forming cells in recipient mice. This finding, by investigators at St. Jude Children's Research Hospital, appears in the Aug. 10 issue of the Proceedings of the National Academy of Sciences (PNAS).
The discovery suggests that this primitive cell could one day be the basis of new medical treatments to replace bone that has been lost to disease or injury, the researchers say.
The St. Jude study was also the first to use a technique called retroviral integration site analysis to prove that a single type of stem cell can give rise to two distinctly different bodily tissues.
The study found strong evidence of a distinct bone marrow cell that is the source of two different lines of cells, one of which produces red and white blood cells, and the other of which helps build bone, according to Edwin Horwitz, M.D., Ph.D., associate member of the St. Jude department of Hematology/Oncology and the divisions of Stem Cell Transplantation and Experimental Hematology.
"Our findings in mice, coupled with previous experience with bone marrow transplantation in humans, suggest that we have identified primitive cells in mice that are responsible for bone repair and regeneration," said Horwitz, senior author of the PNAS report.
The cells identified by the St. Jude team might be especially useful in treating children with a disease such as osteogenesis imperfecta (OI), commonly known as brittle bone disease. OI is a genetic disease that causes extreme fragility of bones, leaving them easily fractured. Children with OI also have deformities and short stature. The problem is caused by a defective gene that fails to produce collagen, the framework of bone.
"The cell we found might also be useful in treating people who have suffered accidents that break or crush bone," Horwitz said.
The researchers used retroviral insertion site analysis to determine which type of bone marrow cell from mice could gave rise to bone-producing cells when transplanted into recipient mice. In this technique, researchers add a piece of DNA, marked with a molecule called "green fluorescent protein" to bone marrow cells taken from donor mice. The added DNA inserts itself randomly into one of the chromosomes and is duplicated each time the cell replicates. The researchers identified the daughter cells of the originally marked cell by locating the marker in the same site of the chromosome in each succeeding generation.
"The major strength of our analysis is the use of retroviral integration site analysis, which unequivocally identified all progeny (descendants of the original cell) that arose from a single cell transplanted into recipient mice," said Massimo Dominici, M.D., the first author of the paper and a postdoctoral fellow in Horwitz's laboratory.
Using this technique, the St. Jude team followed the fates of the cells removed from donor mice and transplanted into recipient mice whose own marrow cells had been destroyed by radiation. The cells identified in this study seem to be better able to engraft in bone than other bone marrow cells called "mesenchymal" cells.
However, osteoblasts--cells that produce bone--that arose from donor cells were detectable for only several months in recipient mice, as occurs in human bone marrow transplant patients. This suggests that bone repair and regeneration during the first few months after transplantation is driven by the transplanted donor cells that engraft (become accepted by the recipient) in bones of the recipient, according to Horwitz. But long-term maintenance of bone strength may be primarily controlled by other cells already present in the recipient's bone.
"This is important to understand because the cells we identified would apparently be useful for repair of diseased or damaged bone in humans," Horwitz said. "But more research is needed to understand how the cells get into the bone and how to manipulate the system to increase the level and duration of engraftment."
Other authors of the study are Colin Pritchard, John E. Garlits, Ted J. Hofmann and Derek A. Persons.
This work was supported in part by a Doris Duke Charitable Foundation Clinical Scientist Development Award; a National Heart, Lung, and Blood Institute Clinical Scientist Award; a National Cancer Institute Cancer Center Support CORE Grant; and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tennessee, St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit http://www.stjude.org.
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