Can exercise prompt your body to generate immune cells in bone marrow? A recent study suggests that the answer is yes.
Scientists have pinpointed a specialized type of bone-cell progenitor in the bone marrow that promotes the generation of immune cells called lymphocytes. Bone marrow contains many types of progenitor and stem cells including progenitors of immune cells. These cells coexist side-by-side. Nearby cells support them by generating specialized protective environments called niches.
Researchers are still studying the interaction between the cells in the niche, also called stromal cells, and the progenitors of immune cells in the bone marrow. Currently, greater insight is necessary to determine how progenitors of immune cells are generated. However, researchers have determined that exercise plays a key role in stimulating communication between one type of stromal cell and immune progenitors in mice, ultimately helping the animals to fight infection.
Osteogenesis and Lymphopoiesis
The wide array of stem and progenitor cells in the bone marrow are interconnected both functionally and physically. For example, progenitor cells, mesenchymal stem cells, fat cells, and skeletal tissue are a key element of the stromal niche for haematopoietic stem and progenitor cells (HSPCs). HSPCs produce all types of blood cells including immune cells.
In mice, some mesenchymal progenitors produce a signaling protein, called stem cell factor (SCF), that is key for supporting HSPCs. These cells produce a cell-surface protein called the leptin receptor (LepR). LepR-expressing (LepR+) cells are found in several crucial locations in bone marrow, including around two types of arterioles, sinusoids, and blood vessels. The researchers in this particular study looked at the subset of LepR+ cells involved in maintaining the HSPC niche.
The scientists conducted a gene-expression analysis of LepR+ cells, which revealed that one subpopulation produces another marker protein, osteolectin (Oln). Amazingly, the scientists produced mice in which their Oln cells would fluoresce. That gave the researchers the ability to determine that Oln stromal cells live in proximity to arterioles but not sinusoids. They further found that the cells are short-lived osteogenic progenitors, which lead to bone-forming cells called osteoblasts. Osteoblasts play a prime role in bone regeneration.
Blood Flow Promotes Liver Growth
These discoveries led the scientists to engineer mutant mice that had no gene encoding SCF in Oln+ cells. This lack of SCF in Oln cells failed to impact haematopoietic stem cells or most other types of haematopoietic progenitor cells in the bone marrow. However, it did lead to a significant reduction in the number of one special type of haematopoietic progenitor — the common lymphoid progenitor (CLP), which leads to production of lymphocytes.
To show that Oln+ cells help to generate and maintain CLPs, the scientists documented that Oln+ cells and CLPs live closely in the bone marrow. Then they introduced a disease-causing bacterium (Listeria monocytogenes) into the mice. Typically, lymphocytes clear this bacterium from the body. The mutant mice cleared the pathogen much less efficiently than did the non-mutated mice. The animals did not produce enough lymphocytes to be effective due to the lower number of CLPs.
Exercise and Bone Formation
Mechanical stimulation of bones due to exercise has been shown to promote bone formation. In the final group of experiments, the scientists housed the mice in cages with running wheels. The found that running in those wheels led to an increase of both Oln+ cells and CLPs in bone marrow.
The researchers found that the Oln+ cells produce the mechanosensitive ion channel protein. In addition, they established that CLP numbers are abnormally low in the mutant mice. Therefore, the scientists discovered a previously unknown path through which exercise triggers SCF expression in osteogenic progenitors. This helped maintain CLPs, which in turn controlled part of the function of the immune system.
From Exercise to Immune Function
The researchers identified a population of bone-cell progenitors that exist with arterioles in the bone marrow of mice and that produce the proteins leptin receptor (LepR) and osteolectin (Oln).
Exercise activates the mechanosensitive ion channel on the surface of these LepR+Oln+ cells. This triggers differentiation of the cells leading to bone formation. And, it leads to the production and secretion of the stem cell factor, which maintains nearby common lymphoid progenitors. Maintenance of the CLP populations enables them to change into lymphocytes that fight bacterial infections.
This discovery that mechanosensitive osteogenic progenitors play a role in fighting bacterial infections is important. Scientists had already determined that exercise can stimulate the immune system.
However, this new study shows why that happens. If the findings apply to humans as well, their research will have direct clinical applications. For instance, the pathway they discovered may be harnessed to develop more effective therapies that strengthen immune-cell output triggered by exercise.
A logical next step would be to determine if voluntary running can improve bacterial clearance in mice. Another key question would look at increasing the numbers of Oln+ cells and CLPs in bone marrow to provide protection against other disease-causing bacteria and viruses, or whether it might also boost vaccination responses.
In another finding, the researchers found that the number of Oln+ niches and the number of CLPs were lower in the bone marrow of 18-month-old mice than in their 2-month-old counterparts. Aged animals are also active, so factors other than reduced movement might contribute to this ageing-related decline.
In future studies, scientists may look into whether the way in which Oln+ niches sense mechanical stimulation changes over time, or whether epigenetic changes (modifications to DNA that can alter gene expression without changing the underlying DNA sequence) in aged Oln+ cells make them less effective in generating signalling molecules.
Final Thoughts
Mechanosensing has been shown to play a role in bone physiology. Now a critical role for mechanosignaling has been found for other cell types, like pancreatic progenitor cells, intestinal stem cells and the endothelial cells that line blood vessels.
We need to learn more about the niches that support stem cells outside the bone marrow, vasculature, and endothelial cells. These are candidates for forming such niches. It is possible that mechanosensing in niche-forming endothelial cells might contribute to the maintenance of other types of stem and progenitor cells. If that proves to be true, this study may have even greater implications for stem-cell biology.
In the meantime, be sure to get out and exercise!
REFERENCES
- Baryawno, N. et al. Cell 177, 1915–1932 (2019).
- Baccin, C. et al. Nature Cell Biol. 22, 38–48 (2020).
- Shen, B. et al. Nature https://doi.org/10.1038/s41586-021-03298-5 (2021).
- Wei, Q. & Frenette, P. S. Immunity 48, 632–648 (2018).
- Zhou, B. O., Yue, R., Murphy, M. M., Peyer, J. G. & Morrison, S. J. Cell Stem Cell 15, 154–168 (2014).
- Qin, L., Liu, W., Cao, H. & Xiao, G. Bone Res. 8, 23 (2020).
- Nieman, D. C. & Wentz, L. M. J. Sport Health Sci. 8, 201–217 (2019).
- Shoji, H., Takao, K., Hattori, S. & Miyakawa, T. Mol. Brain 9, 11 (2016).