Modulation of Functionally Distinct Hematopoietic Stem Cell Niches by PTH

 描述（由申请人提供）：在骨髓微环境中，各种细胞类型贡献不同的小生境来调节造血干细胞（HSC）行为。骨髓中具有相反生态位功能的两种细胞类型是成骨细胞和骨髓脂肪细胞。成骨细胞已被表征为支持性生态位，而一项描述性研究表明，具有膨胀脂肪含量的骨髓腔与HSC含量呈负相关。我的研究生课程旨在研究甲状旁腺激素（PTH）如何激活成骨细胞龛，促进HSC扩增，同时去除骨髓脂肪细胞。我们进行了PTH治疗的体内时间过程（1、3、5和10天）以确定骨髓脂肪细胞消耗的速率（双因素方差分析P=0.0001）。该显著性由PTH治疗的1天和10天驱动（Bonferroni后检验P<0.05）。我们由此推测，两个并发机制可以解释这种现象。这种脂肪细胞群的最初损失可能是由于骨髓细胞消耗了储存的脂质。脂肪细胞群体的持续减少可能是间充质祖细胞远离脂肪细胞命运的定型转变的结果。这将使用两种不同的PTH活化小鼠模型进行研究：间歇性PTH给药的药理学模型和遗传功能获得，其中组成型活性PTH受体在成骨细胞中表达。从这些模型中，我们可以使用流式细胞术和功能测定来确定间充质祖细胞的任何潜在谱系偏好的变化。从代谢的角度来看，我们将研究骨钙素翻译后修饰的变化，因为这种成骨细胞衍生的肽是已知的全身代谢状态的调节剂。该项目的数据将确定骨髓脂肪细胞作为HSC扩增的新治疗靶点。

 DESCRIPTION (provided by applicant): In the bone marrow microenvironment various cell types contribute different niches to regulate Hematopoietic Stem Cell (HSC) behavior. Two cells types within the bone marrow with opposing niche functions are osteoblast and bone marrow adipocytes. Osteoblasts have been characterized as a supportive niche, while one descriptive study has shown that marrow cavities with expanded fat content negatively correlate with HSC content. My graduate studies aim to investigate how activation of the osteoblastic niche by Parathyroid Hormone (PTH) facilitates HSC expansion, while simultaneously removing bone marrow adipocytes. We performed an in vivo time course of PTH treatment (1, 3, 5, and 10 days) to determine the rate at which bone marrow adipocytes are depleted (2-Way ANOVA P=0.0001). This significance was drive by 1 day and 10 days (Bonferroni Post Test P<0.05) of PTH treatment. We hypothesize from this that two concurrent mechanisms may explain this phenomenon. The initial loss of this adipocytic population may by consumption of lipid stores by cells of the bone marrow. Sustained reduction of the adipocytic population may be the result of a commitment shift of the mesenchymal progenitor away from an adipocyte fate. This will be investigated using two distinct murine models of PTH activation: a pharmacologic model of intermittent PTH administration and a genetic gain of function where a constitutively active PTH receptor is expressed in osteoblastic cells. From these models we can use flow cytometry and functional assays to determine changes in any potential lineage bias of mesenchymal progenitors. From a metabolic perspective we will investigate changes in osteocalcin post-translational modifications, as this osteoblast derived peptide is a known modulator of systemic metabolic state. Data from this project would identify marrow adipocytes as a novel therapeutic target, for HSC expansion.