Bone Cells Influence Blood Stem Cell Replication, Migration

Using a novel investigatory technique, researchers at the Joslin Diabetes Center have established that osteoblasts, cells responsible for bone formation, are also directly involved in the proliferation and expansion of blood-forming hematopoietic stem cells.

The finding, published online in May in the journal Blood, improves understanding of how such stem cells work and could have implications for the future of bone marrow and peripheral blood progenitor cell transplants, which are used in the treatment of a variety of illnesses - including leukemia, lymphoma and immunodeficiency. The success of these transplants depends on the ability of intravenously infused blood-forming stem cells, which normally reside predominantly in the bone marrow, to accurately and efficiently migrate from the blood to the marrow of the transplant recipient and, once there, to repopulate their pool of mature blood cells.

"In normal individuals, blood-forming stem cells continually seed the production of all cells in the adult blood system. Appropriate regulation of stem cell activity is essential for maintaining this normal cell replacement, and for supporting repair of the blood system after injury," said lead author Amy J. Wagers, Ph.D., Principal Investigator in the Joslin Section on Developmental and Stem Cell Biology, principal faculty member at the Harvard Stem Cell Institute and Assistant Professor of Stem Cell and Regenerative Biology at Harvard University.

The signals that regulate stem cells remain largely mysterious, but some have been proposed to emanate from specialized cells in the bone marrow environment which form a supportive "stem cell niche" to communicate physiologically relevant signals to stem cells.

A number of earlier studies had implicated bone-lining osteoblasts as important "niche cells." However, these earlier studies were complicated by the presence of other cell types within the bone marrow. As a result, whether osteoblasts in particular could modulate blood-forming stem cell activity remained controversial.

To clarify this issue, Wagers and co-author Shane R. Mayack, Ph.D., Research Fellow in the Joslin Section on Development and Stem Cell Biology, developed a strategy to isolate osteoblasts and then exposed these osteoblasts to bone marrow stem and progenitor cells in vitro to test their ability to alter stem cell proliferation and function.

"The idea was to deconstruct the complexity of the marrow environment to find out whether osteoblasts alone were sufficient to regulate stem cell activity," said Wagers.

In their experiment, the researchers took osteoblasts from normal mice and from mice treated with drugs designed to cause stem cells to proliferate and migrate - a process known as "mobilization." They then exposed the isolated osteoblasts to bone marrow progenitor cells from normal mice in vitro.

The bone marrow cells exposed to the osteoblasts taken from the treated mice proliferated rapidly, while those from untreated mice were inhibited from replicating.

According to Wagers, this effect demonstrates that the osteoblast cells are capable of communicating to the stem cells the physiological signals provided by the drugs.

"It demonstrates that osteoblasts act as functional niche cells capable of directly regulating stem cell activity," she said. "This work provides mechanistic insight into the common process of stem cell mobilization and makes available a new way to discover novel pathways that regulate the expansion of hematopoietic stem cells."

"Additionally, this study establishes a new paradigm for examining more generally how 'support cells' in the body influence stem cell activity," she said.

The new finding also provides an opportunity to study potential changes in niche cells that may contribute to diseases such as leukemia or bone marrow failure, said Wagers.

According to Wagers, future studies will seek to identify the molecular factors necessary for the communication between the osteoblasts and stem cells and to try and understand how changes in that communication system may play a role in the development of disease.