Scientists at the Massachusetts General Hospital (MGH) Center for Regenerative Medicine and the Harvard Stem Cell Institute (HCSI) have defined a molecule that dictates how blood stem cells travel to the bone marrow and establish blood and immune cell production. The discovery may help improve bone marrow stem cell transplantation and the treatment of several blood disorders.
"This is another remarkable example of how bone and bone marrow interact. A receptor known to participate in the body's regulation of calcium and bone also is critical for stem cells to engraft in the bone marrow and regenerate blood and immune cells," says David Scadden, MD, director of the MGH Center for Regenerative Medicine and co-director of the HSCI. "It reminds us how tissues interact and how looking closely at where stem cells reside may tell us a lot about how to manipulate them." Scadden is senior author of the report, which will be published in the journal Nature and has received early online release.
Hematopoietic or blood stem cells are critical to the daily production of over 10 billion blood cells and are the basis for bone marrow transplant therapy for cancer. Rare and difficult to identify, these cells are extremely powerful at regenerating blood and immune cells but only if they travel to the proper location when introduced into the body. Typically the cells are infused into a vein, and they find their way to the bone marrow through a process that depends on largely unknown molecules.
Within the bone marrow cavity, stem cells are usually found in the outer layer close to the inner surface of the bone. Since the process of remodeling bone takes place in the adjacent bone tissue and because studies by Scadden's group and others have shown that bone-forming osteoblast cells are essential to the regulation of the stem cell environment, it seemed probable that fundamental interactions exist between the processes of bone formation and stem cell development. As increased extracellular calcium is required for bone formation, the researchers theorized that a molecule called the calcium-sensing receptor (CaR), present on many cells, might be key to the localization of blood stem cells.
To test their theory, the researchers first verified the presence of CaR on primitive marrow cells taken from normal mice. They then ran several experiments using transgenic mice that do not produce the CaR protein and found that, while many types of marrow and adjacent bone cells were present in normal proportions, levels of blood stem cells were very low in the marrow cavities of the transgenic mice. Other experiments showed that the absence of other cell-surface molecules did not affect the numbers of stem cells in the marrow.
Examination of the spleens and the blood of the transgenic mice showed that the numbers of primitive blood stem cells were significantly elevated in those areas, indicating that the absence of CaR did not affect the production of stem cells by the fetal liver. In a group of normal mice that received radiation at doses that would destroy the bone marrow, transplantation of fetal liver cells from mice with and without CaR allowed the animals to survive, but those who received cells from CaR-negative mice had dramatically fewer stem cells in their bone marrow. Additional experiments showed that the CaR-negative cells were unable to adhere to collagen I, an essential bone protein produced by the osteoblasts.
"Since there are already drugs available that target this receptor, we may be able to quickly adapt these findings in animals to the treatment of human patients," says Scadden, who is a professor of Medicine at Harvard Medical School.
Lead author of the Nature report is Gregor Adams, PhD, of the Center for Regenerative Medicine and HSCI; a group of collaborators from Brigham and Women's Hospital (BWH) was led by Edward Brown, MD. Other co-authors are Karissa Chabner, Ian Alley, Dougas Olson, Zbigniew Szczpiorkowski, MD, and Mark Poznansky, MD, PhD, of the MGH; and Claudine Kos, PhD, and Martin Pollack of BWH. The research was supported by grants from the American Society of Hematology, the Burroughs Wellcome Fund, the Doris Duke Charitable Trust and the National Institutes of Health.
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