Mechanical forces from running and walking that are transmitted along blood vessels in marrow induce the growth of new bone and immune cells in mice, scientists reported in Nature on February 24. The study is the first to demonstrate that mechanical forces can influence cellular growth and differentiation in the bone marrow, according to the authors, and provides a possible new explanation for how exercise strengthens bones and the immune system.
It’s well known that aging weakens bones and running can help strengthen them. “The way that’s understood to work is the mechanical forces are thought to act on the bone itself. And the soft bone marrow inside your bones is going to be insulated from those mechanical forces,” says Sean Morrison, the director of the Children’s Medical Center Research Institute at UT Southwestern and the senior author of the new study. His latest work counters the insulation theory and shows that arteriolar blood vessels that go through the bone surface to the marrow transmit movement-induced mechanical forces and thereby stimulate the proliferation of bone- and immune-cell precursors.
Siddaraju Boregowda, a stem cell biologist at the Scripps Research Institute who was not involved in the work, tells The Scientist in an email that the study is “elegant” and that the researchers “teased out the complexity” of how environmental factors such as exercise influence cell growth in the bone marrow.
The latest study connects the dots between two discoveries Morrison’s team had made in recent years. The first was of a population of cells surrounding the blood vessels that travel through the bone to the bone marrow; it wasn’t initially clear what these cells were doing or how they were interacting with other cells. The other discovery was of a growth factor, which they named osteolectin, that helps maintain bone mass in adult mice by stimulating the formation of bone cells in the marrow.
The researchers weren’t sure how osteolectin was produced, so in the latest study, Bo Shen, a postdoc in Morrison’s lab, used a chemical tag to figure out which cells were producing the growth factor. It turned out they were the cells they’d previously discovered around the arteriolar blood vessels.
I don’t think there’s any stem cell niche in any mammalian tissue that has so far been shown to be mechanically regulated.—Sean Morrison, UT Southwestern
Knowing that bones weaken with age and that both running and osteolectin seem to protect them, Shen and his team wondered if the growth factor was responsible for the exercise benefit. They found that older mice that ran on a wheel produced more osteolectin and more new bone cells compared with older mice that didn’t run. Additionally, the researchers found that as the bone cells grew, they secreted growth factors that encouraged the formation of immune cells, which improved the animals’ ability to fight off bacterial infections.
To see what it was about exercise that stimulated the cells to make the growth factor, the team genetically modified mice so their osteolectin-producing cells would no longer make a receptor, Piezo1, that is known to respond to mechanical forces such as the physical impact of running. With the receptor gone specifically from those cells, the bone and immune cells no longer proliferated in response to exercise.
“The most exciting thing that we found was that these cells around the arteriolars are mechanically regulated—they require mechanical stimulation in order to be maintained,” says Morrison.
David Ferguson, a physiologist at Michigan State University who was not involved in the study, calls the work “massive, impressive, and really well done.” He says his own lab, which studies the effects of exercise on growth and development in mice, will benefit from the results. The authors, he adds, “provided a very nice path for us to look at certain types of cells and environmental factors.”
The results shed light on so-called stem cell niches—specialized environments in the bone marrow that are controlled by growth factors. Very few of the bone marrow’s niches have been studied in depth. Morrison says he was shocked to find that mechanical forces from exercise could play a role in maintaining their conditions.
“I don’t think there’s any stem cell niche in any mammalian tissue that has so far been shown to be mechanically regulated,” says Morrison. “This opens the wider question of whether mechanical stimulation is necessary more often than we thought [to regulate niches].”
B. Shen et al., “A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis,” Nature, doi:10.1038/s41586-021-03298-5, 2021.