Modulation of Functionally Distinct Hematopoietic Stem Cell Niches by PTH

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 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.