In some sense the finding by scientists at the University of Rochester Medical Center, Harvard Medical School and Massachusetts General Hospital may not seem startling – after all, it's long been known that the bone marrow that is the source of all our blood cells is in the center of our longest bones. But the team's paper in the Oct. 23 issue of the journal Nature is the first to pinpoint the role of bone forming cells in controlling the expansion of blood-forming stem cells, and to identify a way to multiply such cells without pushing them along toward their ultimate cell fate.
The finding could be important for bone-marrow-transplant patients, for whom a limit in stem cells often makes the procedure more dangerous if not impossible. By exploiting their knowledge of the bone's role in the creation of blood cells, the team was able to create mice that were nearly four times as likely to survive a difficult transplant as other mice. The bone marrows of the treated mice looked much healthier and were more densely packed with blood cells.
"This started as a rather improbable project, a side project that became more and more interesting as we made our findings," says Laura Calvi, M.D., of the University of Rochester Medical Center, who is the first author and an endocrinologist in the Department of Medicine. "It's especially exciting because the compound we used is already known to work safely in people, so we can start looking quickly to see whether this strategy will work in people too."
Calvi began the work when she was a physician at Massachusetts General Hospital. A physician who specializes in treating patients with osteoporosis, she was curious about the workings of parathyroid hormone, a molecule long known as an important regulator of bone metabolism. A modified form of the compound was approved last year as the medication Forteo for the treatment of osteoporosis.
Calvi had been studying in the laboratory a genetically altered strain of mice whose bodies behaved as if there were a steady stream of the hormone – in other words, the hormone's receptor was always activated in these mice, but only in bone-building cells known as osteoblasts, nowhere else. To understand whether modifying the bone forming cells affected the neighboring hematopoietic cells, she began collaborating with David Scadden, M.D., a hematologist at Massachusetts General with a specific interest in hematopoietic stem cell regulation.
The team found the hormone doubles the bone marrow's output of blood-forming stem cells known as hematopoietic stem cells, from which all our blood cells originate.
The scientists also discovered that bone-building osteoblasts are key to the process, not just giving structure to bone but also affecting the formation of blood cells within. While it was known that parathyroid hormone boosts the numbers of osteoblasts, the scientists pinpointed a molecular signaling system between osteoblasts and stem cells that governs the formation of the stem cells.
"Currently there are medications to expand stem cells, but they cause the cells to differentiate also," says Calvi. "There's not really much you can do to expand the hematopoietic stem cell population. It turns out that it's the osteoblast, right in the bone, that is able to do that."
The ability to expand stem cells would be especially welcome for transplant patients, says Jane Liesveld, M.D., clinical director of the Leukemia, Blood and Marrow Transplant Program at the James P. Wilmot Cancer Center. Sometimes patients or their transplant donors can't produce enough stem cells, making them ineligible for the procedure, which is sometimes a patient's best chance for survival.
Calvi and Scadden's team pinpointed molecular signals known as "Jagged-1" and "Notch" as the key players that bring osteoblasts and stem cells together. The team found that parathyroid hormone not only boosts the number of osteoblasts but also the amount of Jagged-1 on those cells, making them more likely to interact with the Notch molecule on stem cells and spur their expansion.
Notch is well known to stem cell researchers such as hematologist Laurie Milner, M.D., associate professor of Pediatrics and Medical Oncology in the university's Aab Institute of Biomedical Sciences and an author of the Nature paper. She was one of the first people to discover the importance of Notch in stem cells, identifying the molecule as one that helps direct immature blood cells decide their fate. It's Notch that allows a fixed number of stem cells to serve as the font of blood cells that will last a lifetime.
Milner says while there has been some evidence of the involvement of Jagged and Notch in the stem cell process, it wasn't known which of the body's cells besides the stem cells were involved.
"For the most part, hematopoietic stem cells researchers haven't thought that much about osteoblasts, though they're in the bone marrow right next to the blood cells that are developing," says Milner.
Calvi attributes her interest in looking beyond the traditional boundaries of bone researchers partly to her constant contact with a hematologist, her husband Jonathan Friedberg, M.D.
"I look at bone as a bone biologist would," says Calvi. "The osteoblasts provide support and maintain structure. He looks at bone as a source for bone marrow. We had a lot of interesting discussions. Why is it that blood cells are produced in the bone? Is it simply because the bone can provide the space, or is there more to it?"
While working on the project, Calvi moved to Rochester from Harvard in the summer of 2002; she credits a talk by a Rochester colleague, hematologist James Palis, on the origins of blood cells, with putting her on the trail of Notch and Jagged.
"Sometimes you just need to be exposed to something that is foreign, to open your eyes to understand what you've been looking at," Calvi says.
Calvi did the work with funding from the National Institute of Diabetes and Digestive and Kidney Diseases. The research was also funded by the American Society of Hematology, the Doris Duke Foundation, and the Burroughs Wellcome Fund.
In addition to Calvi and Milner, the Rochester authors include technician Jonathan Weber. Authors from Harvard Medical School include M.C. Knight, E. Schipani, P. Divieti, F.R. Bringhurst, H.M. Kronenberg; authors from Massachusetts General Hospital Cancer Center, besides Scadden, were G.B. Adams, K.W. Weibrecht, D.P. Olson, and R.P. Martin.
Journal
Nature