Mechanisms responsible for exercise-induced alterations in hematopoiesis

造血干细胞（HSCs）是造血系统中最原始的细胞，负责整个生命周期中所有成熟血细胞的维持和再生。HSC位于骨髓内，其功能受到其微环境或生态位内的细胞和可溶性因子的调节。间充质基质细胞（MSC）是HSC生态位的主要组成部分。MSC通过分化成成骨细胞或脂肪细胞而贡献于HSC龛的细胞组分。此外，MSC通过产生和分泌直接调节HSC命运的造血生长因子和细胞因子而有助于HSC生态位的可溶性组分。PI实验室发表的数据表明，急性运动和运动训练可改善HSC的数量和功能。我们最近的试验数据表明，MSC是运动诱导HSC改善的关键机制环节。然而，负责MSC在调节HSC响应运动中的作用的精确机制仍有待充分阐明，部分原因是缺乏MSC鉴定的特异性标记物。最近开发的小鼠模型，允许在体内的MSC的前瞻性鉴定，提供了新的工具，用于评估MSC在调节HSC在体内生理条件下，如运动的作用。因此，我们的长期目标是使用HSC作为模型，以更好地了解成体干细胞及其生态位之间的复杂相互作用，以及运动如何调节这些相互作用以影响干细胞的命运。为了实现这一长期目标，我们的短期目标是：*1。确定MSC对HSC小生境的细胞组成改变的贡献。*2。确定运动对MSC分泌旁分泌因子的影响及其在造血中的作用。* 3.确定MSC是否是运动诱导的HSC增殖和动员所必需的。*拟议的实验将结合PI实验室中已经建立的各种体外和小鼠运动模型，以及用于特异性鉴定和消融MSC的新型报告基因和条件性敲除模型。我们希望从拟议的实验结果，以确定新的机制，负责运动诱导的改变血细胞的维持和再生，以及新的分子介质MSC-HSC的串扰。对HSC-生态位相互作用的理解是非常有限的，运动对骨髓微环境的影响是一项原创和创新的研究。拟议的研究将提供独特的培训机会，学员感兴趣的分子运动生理学和干细胞生物学。

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.