25 Mar How exercise affects immune cells in the bone marrow
I will present the results of a paper published in the journal Nature in March this year that shows how exercise affects the production of immune cells in the bone marrow and thus participates in immunoregulation (Shen et al. A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis . Nature. 2021 Mar; 591 (7850): 438-444.).
1. What is bone marrow and what is its function
Bone marrow is tissue found in an adult inside some bones, such as the pelvis, hip and sternum. The bone marrow contains stem cells from which all blood cells develop: erythrocytes, leukocytes and thrombocytes.
The bone marrow is a hematopoietic organ in which new blood cells are formed during life.
However, the bone marrow can also be an immunoregulatory organ because B lymphocytes are formed and mature in the bone marrow. Long-lived antibody-producing plasma cells are mainly found in the bone marrow. Thus, the bone marrow contributes to the antibody-mediated humoral immune response. Although organized areas of T and B lymphocytes are lacking in normal bone marrow, bone marrow is the site of function, migration, and selective retention of innate and adaptive immune cells. The bone marrow is the tissue in which immunoregulatory processes take place and may be a potential therapeutic target for immunotherapy and vaccination.
2. What is the structure of the bone and where is the bone marrow located
Bone is an organ composed of cortical and spongy (trabecular) bone, hematopoietic and connective tissue. The spongy bone is composed of lattices of tiny bone plates filled with hematopoietic tissue, adipose tissue and blood vessels. The bone marrow cavity in the trabecular bone has four regions: endosteal, subendosteal, central, and perisinusoidal. The bone marrow consists of a hematopoietic component (parenchyma) and a vascular component (stroma). The parenchyma includes blood stem cells and hematopoietic progenitor cells, which are localized near the bone endosteum and more around the blood vessels.
Bone marrow stroma contains multipotent nonhematopoietic cells capable of differentiating into various tissues of mesenchymal origin, including osteoblasts, endothelial cells, reticular cells, fibroblasts, and adipocytes. Stromal cells, including endothelial cells, provide signals for the migration of leukocytes into the bone marrow. Compared to other organ-specific endothelial cells, bone marrow endothelial cells constitutively express certain cytokines and adhesive molecules such as VCAM-1 and E-selectin involved in the migration of immune cells into the bone marrow.
3. Which immune cells are present in the bone marrow
The immune system is functionally divided into primary and secondary lymphoid organs where the immune response is triggered and maintained. The bone marrow has a structure similar to secondary lymphoid organs and contains follicles similar to those in the lymph nodes or spleen, although there are no organized areas of T and B lymphocytes. The bone marrow microenvironment provides adequate support for T cells to develop in the absence of the thymus. Lymphoid follicles in the bone marrow increase during infections, inflammation and autoimmunity.
The bone marrow is well vascularized and is part of the network of daily lymphocyte recirculation. The bone marrow contains immune cells. About 8% -20% of bone marrow mononuclear cells are lymphocytes distributed in the stroma and parenchyma and in lymphoid follicles. About 1% of mononuclear cells are plasma cells that produce antibodies. Among T lymphocytes there are CD4 + T cells, CD8 + T cells and approximately one third of CD4 + T cells are CD4 + CD25 + regulatory T (Treg) cells, and the ratio of CD4/CD8 lymphocytes is 1 ∶ 2, which is the opposite compared to peripheral lymph nodes and blood.
Two-thirds of bone marrow T cells have surface markers that indicate prior contact with antigens, have a memory cell phenotype, such as CD44hi and CD122 +, while most T cells in the spleen and peripheral lymph nodes have a naive T cell phenotype. There are CD11c + dendritic cells and NKT cells in the bone marrow. The presence of immune cells suggests that the bone marrow is a lymphoid organ that can play key roles in the function of the immune system.
There are many types of stem and progenitor cells in the bone marrow, including progenitors of immune cells, which coexist in parallel with stromal cells, but how their interaction takes place is largely unknown. Knowledge of how these cell interactions are coordinated will help us better understand how immune cell progenitors are created in the bone marrow.
In the work of Shen et al. the authors solved one part of this puzzle by discovering that movement stimulates communication between one type of stromal cells and lymphoid progenitor cells in experimental mice, resulting in a more effective defense against bacterial infection.
4. What cells and factors affect the formation of lymphocytes in the bone marrow
Different types of stem and progenitor cells are physically and functionally interconnected in the bone marrow. For example, mesenchymal stem and progenitor cells, which make bone, bone tissues and adipose tissue, are an essential part of the so-called stromal niche for hematopoietic stem and progenitor cells (HSPC). HSPCs are responsible for the production of all types of blood cells, including immune cells. In mice, as shown in this paper, some mesenchymal progenitor cells produce a signaling protein, called stem cell factor (SCF), which is crucial for HSPC. These mesenchymal progenitor cells express a protein on their membrane, the leptin receptor (LepR). LepR + cells are found on several sites in the bone marrow, including sites around two types of blood vessels, arterioles and sinusoids.
However, the LepR + population is a mixture of different types of mesenchymal progenitors.
Gene analysis of LepR + cells has shown that one subpopulation of LepR + cells also expresses a protein, osteolectin (Oln). Oln + stromal cells are located around the arterioles, but not the sinusoids. Oln + stromal cells are short-lived cells and they are osteogenic progenitors of osteoblasts, cells that form bones and play a crucial role in bone regeneration.
The authors of this paper made mutant mice that lacked a gene encoding stem cell factor (SCF) in Oln + cells. The consequence was a lack of SCF in Oln + cells which did not affect hematopoietic stem cells or most other types of hematopoietic progenitors in the bone marrow. However, these mutant mice had a significantly reduced number of one type of hematopoietic progenitor – the common lymphoid progenitor (CLP), from which lymphocytes are formed. In support of the idea that Oln + cells help generate and maintain CLPs, the authors showed that Oln + stromal cells and CLP cells reside close to each other in the bone marrow.
They then infected the mutant mice with the bacterium Listeria monocytogenes, during which infection lymphocytes play a key role in removing this bacterium from the body. Mutant mice removed this bacterium significantly less efficient compared to control mice. The reason for the lower efficacy in fighting this infection in mutant mice was the lower number of lymphocytes due to the reduced number of CLPs in the bone marrow.
5. How exercise affects the formation of lymphocytes in the bone marrow
Mechanical bone stimulation, which exists during exercise, is known to promote bone formation. In this paper, the authors showed that mechanical bone stimulation promotes the formation of lymphocyte progenitors in the bone marrow. The experimental mice ran in their cages on the wheel and this exercise increased the number of both Oln + cells and CLP in the bone marrow. The question was raised by what mechanisms this is achieved. Oln + cells express the mechanosensitive ion channel of the Piezo1 protein, and mice lacking this protein had an abnormally low number of CLPs in the bone marrow.
Thus, the authors discovered a previously unknown pathway by which excercise, through the mechanosensitive protein Piezo1, triggers SCF expression in Oln + osteogenic progenitors thereby maintaining lymphocyte progenitors (CLPs), and thereby control part of immune system function.
Figure: From exercise to improving the function of the immune system. Shen et al. have identified a population of bone cell progenitors located along blood vessels called arterioles in the bone marrow of mice and expressing the leptin receptor (LepR) and osteolectin (Oln). Movements, such as exercise, lead to mechanical stimulation of the bones, activating the mechanosensitive ion channel Piezo1 on the surface of these LepR + Oln + cells, which has two effects. First, it initiates the differentiation of osteoblasts that lead to bone formation. Second, it triggers the expression and secretion of a signaling molecule called stem cell factor (SCF), which helps maintain a common lymphoid progenitor (CLP). The maintenance of CLP populations allows them to differentiate into lymphocytes that participate in the defense against bacterial infections.
The discovery in this paper that mechanosensitive osteogenic progenitors play a role in the fight against bacterial infection is a new finding. It was known that physical activity can stimulate the functions of the immune system, but this paper reveals for the first time the mechanism of how the process takes place. If this finding proves to be relevant to humans, it could have direct clinical applications. For example, the mechanism discovered in this paper could be used for a therapeutic procedure to enhance lymphocyte function. It remains to be investigated whether exercise increases the ability to defend against other bacterial or viral infections, as well as during vaccination.
The authors showed that the number of Oln + cells, and thus the number of CLPs, decreases with age. It is unknown what is the mechanism and whether epigenetic changes (modifications to DNA that can alter gene expression without altering the underlying DNA sequence) in aged Oln + cells cause these cells to become less efficient in generating signaling molecules such as SCF.
Mechanosensitivity has been shown in bone physiology, but it also plays a crucial role for other cell types – for example, pancreatic stem cells, intestinal stem cells and vascular endothelial cells. Although less is known about the niches that support stem cells outside the bone marrow, the vasculature, and thus endothelial cells, are the main candidates for the formation of such niches.
It is possible, therefore, that mechanosensitive endothelial cells that form niches may contribute to the maintenance of other types of stem cells and progenitor cells. If this proves to be the case in future research, this paper could have broad implications for stem cell biology.
If you have questions, comments and suggestions for topics I will be happy to answer.
Shen B, Tasdogan A, Ubellacker JM, Zhang J, Nosyreva ED, Du L, Murphy MM, Hu S, Yi Y, Kara N, Liu X, Guela S, Jia Y, Ramesh V, Embree C, Mitchell EC, Zhao YC, Ju LA, Hu Z, Crane GM, Zhao Z, Syeda R, Morrison SJ. A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature. 2021 Mar;591(7850):438-444. doi: 10.1038/s41586-021-03298-5. Epub 2021 Feb 24. PMID: 33627868; PMCID: PMC7979521