|Abstract:||Hematopoiesis is the process by which mature cells of the hematopoietic system are replenished. Hematopoietic stem and progenitor cells (HSPCs) are responsible for the maintenance and generation of blood cells in circulation. HSPCs primarily reside within the bone marrow (BM) in distinct niches that secrete soluble cytokines, growth factors, or utilize cell-to-cell interaction to regulate HSPC activity. The bone marrow niche is comprised of multiple cell lineages including endothelial cells, mesenchymal stromal cells (MSCs), and marrow adipose tissue (MAT). Previous reports on the influence of age and diet on the BM suggest a role for lifestyle factors in modulating hematopoiesis and HSPC function, creating a more dysregulated environment more conducive to malignant disease. Exercise training influences the BM architecture and HSPCs; and however, a paucity of data exists detailing how exercise may be utilized as a potential therapeutic option in disease models, such as cancer. Thus, the purpose of this thesis was to investigate the role of exercise in modulating the BM niche and HSPCs in disease models of cancer.
This dissertation is divided into four sections. First, we review the literature available pertaining to exercise, BM microenvironment, and hematopoiesis. Subsequently, for our first experiments we determined whether an acute bout of exercise bout of exercise was sufficient to influence the BM compartment. To establish the influence of exercise, we measured the proliferation of HSPCs and BM MSCs via bromo-deoxydurine (BrdU) incorporation and utilized cytokine arrays to determine if the stromal cell secretome. We observed that an acute bout of exercise stimulated the proliferation of both HSPCs and BM MSCs, and altered the secretome of MSCs to promote factors that stimulated proliferation and mobilization of HSPCs. Following our establishment that exercise modulates the bone marrow compartment, we next moved to characterize if exercise could be used as a therapeutic intervention in a cancer model. Colorectal cancer (CRC) is characterized by skewing of HSPCs down myeloid lineages that increase the progression of CRC, and the progression is exacerbated in obesity. We utilized exercise training as a therapeutic intervention in an AOM model of CRC following consumption of a high fat diet, and measured if the exercise training minimized the hematopoietic burden. We observed that CRC and obesity conferred long-term deficits to primitive HSPCs, and these biases were mostly reversed with exercise training. More importantly, we observed that exercise training drastically remodeled the bone marrow compartment and reversed the pro-inflammatory environment associated with obesity and CRC, thereby attenuating the persistent inflammatory stress to HSPCs. In the final section, we wished to establish if exercise would protect the BM and HSPCs from more direct stressors, and modulate risk for secondary malignancy. We utilized a mouse model of leukemia by exposing CBA mice to a sub-lethal bout of ionizing radiation. We observed the protective effects of exercise training by increasing, as measured by increased hematopoietic recovery following IR. More importantly, we observed exercise protected the BM niche and resident stromal cell population while increasing the accumulation of BM fat. Finally, we observed that exercise training, in the presence of obesity, decreases the inflammatory contributions of stromal cells to the BM niche, reducing BM stress and pre-leukemia associated cytokines.
In summary, we show that exercise training influences the bone marrow microenvironment and hematopoiesis in disease. Moreover, we show that obesity and exercise training directly influence the bone marrow microenvironment, and for the first time, exercise training reduces inflammation of the bone marrow. In turn, these data will assist in the development of how exercise reduces cancer risk and development of exercise based interventions.