Stronger bone and better immune protection? Exercise more!

Abstract

Exercise maintains a subset of bone marrow stromal cells that give rise to osteoblasts and lymphoid progenitors. Exercise maintains a subset of bone marrow stromal cells that give rise to osteoblasts and lymphoid progenitors. CITATIONS Shen B, Tasdogan A, Ubellacker JM, et al. A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature. 2021;591 (7850):438–444. The health benefits of exercise have been well documented and publicized, although whether and how exercise improves the fitness of the immune system, consequently leading to better protection against infections, have been less studied. But this is a highly relevant topic in transplantation, since patients with organ transplants often suffer from a variety of transplant-related complications that restrain their physical activities. Thus, studies in this area clearly have the potential to benefit transplant patients. In a recent paper in Nature, Shen et al. initially set out to investigate the bone marrow stromal cell niches that support osteogenesis and adipogenesis in a mouse model, but discovered a subset of peri-arteriolar stromal cells that support lymphopoiesis in adult bone marrow. Interestingly, maintenance of this unique stromal cell subset demands mechanical stimulation of the bone, including exercise, and its targeted deletion in vivo results in markedly impaired lymphoid progenitor development, bacterial clearance, and host survival after acute bacterial infections. Stromal cells that express the leptin receptor (LepR+) are a major source of growth factors that support hematopoietic stem cells and their committed progenitor cells in the bone marrow, but stromal cells are extremely heterogeneous in terms of their functions and localizations. The authors created Osteolectin-mTomato knock-in (OlnmT) mice to genetically mark the LepR+ cells with the tomato red fluorochrome, asking whether osteolectin expression would resolve functionally different LepR+ cells. They found that the Oln-mTomato+ cells were exclusively confined to the peri-arteriolar region in the bone marrow, while they were conspicuously absent in the peri-sinusoidal area. Such peri-arteriolar Oln-mTomato+ cells were highly enriched for the expression of osteogenic genes, whereas the peri-sinusoidal Oln-mTomato- cells preferentially expressed adipogenic genes. Consequently, when stimulated to differentiate, the Oln-mTomato+LepR+ cells gave rise to significantly more osteoblasts and fewer adipocytes than did Oln-mTomato-LepR+ cells. Moreover, fate mapping experiments using the OlniCreERRosa26loxp-tdTomato model demonstrated similar findings, showing that a substantial number of new osteoblasts developed from peri-arteriolar Oln+ cells upon tamoxifen treatment. They concluded that the Oln+ cells in the marrow are committed to form bone, not fat tissues. The authors also observed that Oln+ cells and Oln- cells expressed similar levels of stem cell factor (SCF), a growth factor critical to stem cell survival in the bone marrow. Interestingly, conditional deletion of Scf from Oln+ cells in OlniCreERScff/f mice significantly reduced the frequency of common lymphoid progenitors (CLPs), while other stem cells and committed progenitor cells were not affected, thus suggesting the presence of a peri-arteriolar niche created by the Oln+ cells specifically for CLPs. Indeed, treatment of OlniCreERScff/f mice with tamoxifen for a prolonged period broadly depleted the lymphoid progenitors including CLPs. The authors also showed that bone fractures selectively increased the frequency of Oln-mTomato+ cells and CLPs in the bone marrow, but aging effectively depleted the Oln+ cells, and subsequently the CLPs. They provided extensive evidence that in aged mice, physical exercise could restore the Oln+ cells as well as the peri-arteriolar niche, which then supports CLPs and lymphopoiesis in the aged hosts. They further showed that Oln+ cells express the stretch-induced ion channel protein PIEZO1 and that exercise stimulated the ion channel activities in Oln+ cells, which also led to increased skeletal bone mass. Lastly, the authors determined whether the peri-arteriolar Oln+ cell niche plays any role in clearance of bacterial infections that depend on T and B cells and found that infection of OlniCreERScff/f mice with Listeria (3 days after tamoxifen treatment) led to markedly reduced lymphocyte counts in the periphery, which was accompanied by impaired Listeria clearance and reduced host survival, compared to similarly treated littermate controls. Importantly, the impaired bacterial clearance could be substantially improved upon exercise. They speculated that the mechanism behind their findings is that the arterioles may be particularly conducive to transmitting mechanical stimuli from the bone into the bone marrow to maintain the peri-arteriolar Oln+ cell niche. Clearly, these novel findings suggest the potential to improve the immune fitness of transplant patients.