Mechanisms responsible for exercise-induced alterations in hematopoiesis

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Hematopoietic (blood-forming) stem cells (HSCs) are the most primitive cells of the hematopoietic system, and are responsible for the maintenance and regeneration of all mature blood cells throughout the lifespan. HSC are located within the bone marrow, and their function is regulated by cellular and soluble factors within their microenvironment or niche. Mesenchymal stromal cells (MSCs) are a primary component of the HSC niche. MSCs contribute to the cellular components of the HSC niche by differentiating into osteoblasts or adipocytes. Additionally, MSCs contribute to the soluble components of the HSC niche by producing and secreting hematopoietic growth factors and cytokines that directly regulate HSC fate. Published data from the PI's lab has demonstrated that acute exercise and exercise training improves HSC quantity and function. Our recent pilot data implicates MSCs as a key mechanistic link responsible for exercise-induced improvements in HSCs. However, the precise mechanisms responsible for the role of MSCs in regulating HSCs in response to exercise remain to be fully elucidated due, in part, to a lack of specific markers for MSC identification. Recently developed mouse models that allow for prospective identification of MSCs in vivo, have provided new tools for evaluating the role of MSCs in regulating HSC in vivo under physiological conditions, such as exercise. As such, our long-term objective is to use HSCs as a model to develop a better understanding of the complex interactions between adult stem cells and their niche, and how exercise may modulate these interactions to influence stem cell fate. To achieve this long-term objective, our short-term aims are to:***1. Determine the contribution of MSCs to alterations in the cellular composition of the HSC niche. ***2. Identify the effects of exercise on paracrine factor secretion from MSCs and their role in hematopoiesis.***3. Determine if MSCs are necessary for exercise-induced HSC proliferation and mobilization.***The proposed experiments will combining a variety of in vitro and mouse exercise models already established in the PI's lab with novel reporter and conditional knock-out models for specific identification and ablation of MSCs. We expect outcomes from the proposed experiments to identify novel mechanisms responsible for exercise-induced alterations in blood cell maintenance and regeneration, as well as novel molecular mediators of MSC-HSC cross-talk. The understanding of HSC-niche interactions is extremely limited, and the effects of exercise on the bone marrow microenvironment is an original and innovative line of research. The proposed studies will provide unique training opportunities for trainees interested molecular exercise physiology and stem cell biology.