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.
Hematopoietic stem cells, (HSCs) are at the apex of the hematopoietic hierarchy and their function is highly regulated through interactions with the surrounding bone marrow microenvironment, or niche, particularly osteoblastic cells. While osteoblasts represent a supportive HSC niche, bone marrow adipocytes have been characterized as negative regulators of the HSC niche. This is of interest as osteoblast and bone marrow adipocytes are believed to be derived from the same mesenchymal progenitor and represent niches with opposing roles. We have observed that activation of the niche by Parathyroid Hormone (PTH), which acts in part on osteolineage cells, leads to a rapid depletion of visible bone marrow adipocytes. We therefore hypothesize that PTH activates the HSC niche in part by removing this inhibitory component. These proposed studies here will determine how PTH alters adipocytic content of the marrow, and targeting of these adipocytes may be a novel cellular target of niche activation to expand HSCs.
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