Modulation of Functionally Distinct Hematopoietic Stem Cell Niches by PTH

 描述(申请人提供)：在骨髓微环境中，不同类型的细胞对调节造血干细胞(HSC)的行为有不同的作用。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。成骨细胞一直被认为是一个支持性的利基，而一项描述性研究表明，脂肪含量扩大的骨髓腔与HSC含量呈负相关。我的研究生研究旨在研究甲状旁腺激素(PTH)如何激活成骨细胞壁龛，促进HSC的扩张，同时去除骨髓脂肪细胞。我们进行了体内甲状旁腺素治疗(1、3、5和10天)，以确定骨髓脂肪细胞的耗尽率(2因素方差P=0.0001)。这一意义是由甲状旁腺激素治疗1天和10天(Bonferroni Post Test P&lt；0.05)驱动的。我们由此假设，两种并行机制可以解释这一现象。这种脂肪细胞群体最初的丧失可能是由于骨髓细胞消耗脂肪储存。脂肪细胞数量的持续减少可能是间充质祖细胞承诺远离脂肪细胞命运的结果。这将使用两种不同的甲状旁腺素激活的小鼠模型进行研究：一种是间歇给药的药理学模型，另一种是在成骨细胞中表达固有活性的甲状旁腺素受体的遗传功能获得模型。从这些模型中，我们可以使用流式细胞术和功能分析来确定间充质祖细胞任何潜在的谱系偏向的变化。从代谢的角度，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多肽是已知的全身代谢状态的调节器。来自该项目的数据将确定骨髓脂肪细胞作为一种新的治疗靶点，用于扩增HSC。

 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.