It is quite busy in the bone marrow. Many types of stem and progenitor cells, including immune cell progenitors, coexist12 and are supported by nearby cells that create specialized protective environments for the stem cells called niches. The interplay between the cells of the niche, also called stromal cells, and early precursors of immune cells in the bone marrow is poorly understood. Understanding how this interplay is coordinated would help us to better understand how progenitors of immune cells are generated. Register in Nature, Shen et al3 solved part of the puzzle by identifying a role for movement in stimulating communication between one type of stromal cell and immune precursors in mice, ultimately helping the animals fight infections.
The different types of stem and progenitor cells in the bone marrow are strongly linked, both physically and functionally. For example, mesenchymal stem and progenitor cells, from which bone, skeletal tissue and fat cells develop, are an essential part of the stromal niche for hematopoietic stem and progenitor cells (HSPCs). HSPCs, in turn, are responsible for the production of all blood cell lines, including immune cells4In mice, some mesenchymal precursors produce a signal protein called stem cell factor (SCF) that is crucial for supporting HSPCs5These cells also express a cell surface protein called the leptin receptor5 (LepR). LepR expressing (LepRcells are located in several different locations in the bone marrow, including about two types of blood vessels, arterioles and sinusoids. The LepR population is a mixture of mesenchymal progenitor cells5Shen et alOn the way home in the subset of LepR cells involved in maintaining the HSPC niche.
The authors performed a gene expression analysis of LepR cells, showing that one subpopulation also expresses another marker protein, osteolectin (Oln). The group generated mice in which these Oln cells fluorescent, and found that Oln stromal cells are located around arterioles but not near sinusoids. They then showed that the cells are transient osteogenic precursors, causing bone-forming cells called osteoblasts, which play a critical role in bone regeneration.
Shen and colleagues then developed mutant mice to lack the gene encoding SCF in Oln cells. The resulting lack of SCF in Oln cells did not affect hematopoietic stem cells or most other types of hematopoietic progenitor cells in the bone marrow. However, it led to a significant decrease in the number of one special type of hematopoietic progenitor cells – the common lymphoid progenitor cells (CLP), which give rise to immune cells called lymphocytes. In support of the idea that the Oln cells assist in the generation and maintenance of CLPs, the authors showed that Oln cells and CLPs are located close to each other in the bone marrow. They then infected the mutant mice with a pathogenic bacteria, Listeria monocytogenes, which is usually removed from the body by lymphocytes. The mutant animals released the pathogen much less effectively than the controls. The animals simply did not produce enough lymphocytes to do the job, due to the reduced number of CLPs.
Mechanical stimulation of bones that occurs during exercise is known to promote bone formation6In a final set of experiments, Shen et al. placed mice in cages with running wheels and found that running led to a higher number of both Oln cells and CLPs in bone marrow. The group discovered that the Oln cells express the mechanosensitive ion channel protein Piezo1 and showed that CLP numbers are abnormally low in mice designed to lack this protein. Thus, the authors uncovered a previously unknown pathway by which exercise, sensed by the mechanosensitive protein Piezo1, triggers SCF expression in osteogenic precursors to help maintain CLPs, thereby controlling some of the immune system function (Figure 1).
Figure 1 | From exercise to immune function. Shen et al3 have identified a population of bone cell precursors that reside in the bone marrow of mice next to blood vessels called arterioles and express the proteins leptin receptor (LepR) and osteolectin (Oln). Movements, such as exercise, lead to mechanical stimulation of bones, causing the mechanically sensitive ion channel Piezo1 on the surface of this LepROln cells. This has two effects. First, it triggers differentiation of the cells, which leads to bone formation. Second, it leads to the expression and secretion of a signaling molecule called stem cell factor (SCF), which helps maintain nearby common lymphoid progenitor cells (CLPs). By preserving the CLP populations, they can easily differentiate into cells of the immune system called lymphocytes that can fight bacterial infections.
The discovery that mechanosensitive osteogenic precursors play a role in fighting bacterial infections is exciting. Exercise was known to stimulate the immune system7, but advances in the work of Shen and colleagues provide a reason why this is the case. If relevant to humans, the work could have direct clinical applications. For example, the path uncovered in current research could be used to develop better therapies to boost the output of immune cells activated by movement. A logical next step will be to test whether voluntary running can indeed improve bacterial clearance in mice. Another important question to be answered is whether the number of Oln cells and CLPs in bone marrow may help protect against other pathogenic bacteria, or even viruses, or may also enhance vaccination responses.
The authors also found that the number of Oln niches, and the number of CLPs, was lower in the bone marrow of 18-month-old mice than in their 2-month-old counterparts. Elderly animals are also active8, so factors other than decreased movement can contribute to this aging-related decline.
For example, it would be interesting to investigate the way Oln niches sense changes in mechanical stimulation over time, or that epigenetic changes (adaptations to DNA that can change gene expression without changing the underlying DNA sequence) in obsolete Oln cells make them less effective in generating signaling molecules such as SCF.
Mechanosensing is well established to play a role in bone physiology, but a critical role for mechanosignalization has also been described for other cell types – for example, pancreatic progenitor cells, intestinal stem cells, and the endothelial cells that line blood vessels. While less is known about the niches that support stem cells outside of the bone marrow, the vasculature, and thus the endothelial cells, are the prime candidates for forming such niches. Thus, it is possible that mechanosensing in niche-forming endothelial cells may contribute to the maintenance of other types of stem and progenitor cells. If so, the work of Shen and his colleagues could have profound implications for stem cell biology.