Exercise generates immune cells in the bones

There are enough people in the bone marrow. Many types of stem and progenitor cells, including immune cell progenitors, coexist side by side^1,2 and are supported by neighboring cells that generate specialized protective environments for stem cells, called niches. The interaction between niche cells, also called stromal cells, and the early progenitors of immune cells in the bone marrow is poorly understood. Insight into how this interaction is coordinated would help us better understand how immune cell progenitors are generated. Write in Nature, Shen et al.³ solved part of the puzzle by identifying a role for movement in stimulating communication between a type of stromal cell and immune progenitors in mice, ultimately helping animals fight infection.

The different types of stem and progenitor cells in the bone marrow are highly interconnected, both physically and functionally. For example, mesenchymal stem and progenitor cells, which give rise to bone, skeletal tissue, and fat cells, are an essential part of the stromal niche of hematopoietic stem and progenitor cells (HSPC). HSPCs, in turn, are responsible for the production of all blood cell lines, including immune cells.⁴. In mice, certain mesenchymal progenitors produce a signaling protein, called stem cell factor (SCF), which is crucial in supporting HSPCs⁵. These cells also express a cell surface protein called the leptin receptor.⁵ (LepR). LepR expression (LepR⁺) cells reside in several distinct places in the bone marrow, including around two types of blood vessels, arterioles and sinusoids. However, the LepR⁺ the population is a mixture of types of mesenchymal progenitor cells⁵. Shen et al. left to focus on the LepR subset⁺ cells involved in maintaining the HSPC niche.

The authors performed a LepR gene expression analysis⁺ cells, which revealed that a subpopulation also expresses another marker protein, osteolectin (Oln). The group generated mice in which these Oln⁺ fluorescent cells, and found that Oln⁺ stromal cells reside around arterioles but not sinusoids. They then demonstrated that the cells are short-lived osteogenic progenitors, which give rise to bone-forming cells called osteoblasts that have a crucial role in bone regeneration.

Shen and his colleagues then designed mutant mice not to have the gene encoding SCF in Oln.⁺ cells. The resulting lack of SCF in Oln⁺ the cells did not affect hematopoietic stem cells or most other types of hematopoietic progenitor cells in the bone marrow. However, this led to a significant reduction in the number of a special type of hematopoietic progenitor – the common lymphoid progenitor (CLP), which gives rise to immune cells called lymphocytes. In support of the idea that the Oln⁺ cells help generate and maintain CLP, the authors demonstrated that Oln⁺ cells and CLPs reside closely together in the bone marrow. They then infected the mutant mice with a pathogenic bacteria, Listeria monocytogenes, which is usually cleared from the body by lymphocytes. Mutant animals cleared the pathogen much less efficiently than controls. The animals simply did not produce enough lymphocytes to do the job, due to the reduced number of CLP.

Mechanical bone stimulation, which occurs during exercise, is known to promote bone formation⁶. In a final series of experiments, Shen et al. placed mice in cages equipped with running wheels, and found that running resulted in a higher number of Oln⁺ cells and CLP in the bone marrow. The group found that the Oln⁺ the cells express the mechanosensitive ion channel protein Piezo1 and have shown that CLP numbers are abnormally low in mice designed to lack this protein. Thus, the authors discovered a previously unknown pathway by which exercise, detected by the mechanosensitive protein Piezo1, triggers expression of SCF in osteogenic progenitors to help maintain CLP, thereby controlling part of the function of the immune system. (Fig. 1).

The discovery that mechanosensitive osteogenic progenitors have a role in the fight against bacterial infections is exciting. We knew that movement could stimulate the immune system⁷, but the advancements in the work of Shen and his colleagues provide a reason why this is the case. If relevant to humans, the work could have direct clinical applications. For example, the path discovered in the current study could be exploited to develop better therapies to boost the production of immune cells triggered by movement. A logical next step will be to test whether voluntary functioning can actually improve bacterial clearance in mice. Another key question to be addressed will be whether the increase in the number of Oln⁺ cells and CLPs in the bone marrow would help provide protection against other pathogenic bacteria, even viruses, or could also stimulate vaccine responses.

The authors also found that the number of Oln⁺ niches, and CLP counts, were lower in the bone marrow of 18-month-old mice than in their 2-month-old counterparts. Older animals are also active⁸, factors other than reduced movement could therefore contribute to this aging-related decline.

It would be interesting to examine, for example, whether the way in which Oln⁺ niches detect changes in mechanical stimulation over time, or if epigenetic changes (DNA changes that can alter gene expression without changing the underlying DNA sequence) in older Oln⁺ cells make them less efficient at generating signaling molecules such as SCF.

Mechanosensing is well established to play a role in bone physiology, but a crucial role for mechano-signaling has also been described for other cell types – for example, pancreatic progenitor cells, intestinal stem cells and the endothelial cells that line the blood vessels. While less is known about the niches that support stem cells outside of the bone marrow, the vascular system, and therefore endothelial cells, are prime candidates for forming such niches. It is therefore possible that mechanodetection 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 broad implications for stem cell biology.