Scientists at the Research Institute of the University of Texas Southwestern Children’s Medical Center (CRI) have identified the specialized environment, known as a niche, in the bone marrow where new bone and immune cells are produced.
The study, published in the journal Nature, also shows that stimulation induced by movement is necessary for the maintenance of this niche, as well as the bone and immunity-forming cells it contains. Together, these findings identify a new way in which exercise strengthens bones and immune function.
Researchers in Professor Morrison’s lab found that forces caused by walking or running are transferred from bone surfaces along arteriolar blood vessels to the marrow in the bones. The bone-forming cells lining the outside of the arterioles sense these forces and are prompted to proliferate.
Not only does this allow new bone cells to form, making the bones thicker, but the bone-forming cells also secrete a growth factor that increases the frequency of the cells that form lymphocytes around the arterioles. Lymphocytes are the B and T cells that the immune system can use to fight infections.
When the ability of bone-forming cells to sense the pressure caused by movement, also called mechanical forces, was inactivated, the formation of new bone cells and lymphocytes was reduced, causing the bones to thin and the ability of mice to clear a bacterial infection.
“As we age, our bone marrow environment changes and the cells responsible for maintaining skeletal bone mass and immune function become depleted. We know very little about how this environment changes or why these cells decline with age, ” said Sean Morrison, director of the CRI and researcher at the Howard Hughes Medical Institute. Previous research has shown that exercise can improve bone strength and immune function, and our study has uncovered a new mechanism by which this happens. “
Previous work from Morrison’s lab discovered the skeletal stem cells that give rise to most of the new bone cells that form in the bone marrow during adulthood. They are leptin receptor + (LepR +) cells. They form the outside of blood vessels in the bone marrow and are critical growth factors for the maintenance of blood-producing cells.
Morrison’s lab also found that a subset of LepR + cells synthesize a previously undiscovered bone-forming growth factor called osteolectin. Osteolectin promotes the maintenance of the adult skeleton by causing LepR + to form new bone cells.
In the current study, Bo Shen, a postdoctoral researcher in Morrison’s lab, took a closer look at the subset of LepR + cells that produce osteolectin. He found that these cells are located exclusively around the arteriolar blood vessels in the bone marrow. and that maintain narrow lymphoid precursors by synthesizing stem cell factor (SCF), a growth factor on which these cells depend.
Removal of SCF from osteolectin-positive cells depleted lymphoid progenitors and undermined the ability of mice to mount an immune response to bacterial infection.
“Together with our previous work, the findings of this study demonstrate that osteolectin-positive cells are creating a specialized niche for lymphoid and bone-forming precursors around the arterioles,” said Shen. Osteolectin positive cells can enhance bone formation and immune responses, especially in the elderly. “
Shen found that the number of lymphoid progenitor cells and cells positive for osteolectin decreased with age. Wondering if she could reverse this trend, she put wheels on the cages so the mice could train. He found that the bones of these mice were strengthened with exercise, while the number of osteolectin-positive cells and lymphoid progenitor cells around the arterioles increased. This was the first indication that mechanical stimulation regulates a niche in the bone marrow.
He found that cells positive for osteolectin expressed a receptor on their surface, known as Piezo1, that sends signals to the cell in response to mechanical forces. When Piezo1 was removed from cells in osteolectin-positive mice, these cells and the lymphoid progenitors that support them were depleted, weakening bones and altering the immune response.
“We believe we have found an important mechanism by which exercise promotes immunity and strengthens bones, in addition to other mechanisms previously identified by others,” notes Morrison.