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Deletion of Vhl in Dmp1-expressing cells causes microenvironmental impairment of hematopoiesis

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How changes in bone homeostasis affect immune development is not fully understood. The von-Hippel Lindau protein (VHL) regulates hypoxia-inducible factor (HIF) degradation, which is involved in cellular adaptation to low oxygen environments. Conditional deletion of Vhl in osteoblasts and hematopoietic progenitors have demonstrated a role for VHL in these cell types. Studies have demonstrated that the B cell development is mediated by crosstalk between the skeletal and hematopoietic systems. To understand how changes in bone homeostasis may affect immune cell development, we utilized Dmp1-Cre;Vhlfl/fl conditional knockout mice (VhlcKO), in which Vhl is deleted primarily in osteocytes, mature osteoblasts, and a small subset of MSCs. The VhlcKO mice display dysregulated bone growth, high bone density, smaller bone marrow (BM) cavity volume, and an overall decrease in BM cellularity compared to wild-type (WT) controls. In line with this, the frequencies, and numbers of B cells in the BM were significantly decreased. These data suggest that changes in bone homeostasis may adversely affect B cell development in a cell-extrinsic manner. We hypothesized that normal B cell development was not supported in VhlcKO mice due to alterations of the microenvironment niche, such as reduction of key niche cells and decreased production of B cell-supporting cytokines. Furthermore, we have obtained evidence that Vhl deletion also affects myeloid and erythroid development. We found elevated Epo levels in cKO peripheral blood serum and BM fluid by 6 weeks of age, and evidence for dysregulated erythropoiesis. Moreover, the cKO displayed an increased frequency of common myeloid progenitors, CD11b+ Gr1- monocytes, and CD11b+ Gr1+ granulocytes by 10 weeks of age. We also hypothesized that alterations in skeletal glucose metabolism directly affect myeloerythroid development in the BM through increased Epo-receptor (EpoR) signaling. EpoR is expressed on osteoprogenitors, hematopoietic stem cells, and B cells, but whether it is expressed on myeloid progenitors is unclear. Studies are in progress to test the hypothesis that overproduction of Epo by Vhl-deficient Dmp1+ cells result in elevated EpoR signaling in myeloid progenitors and lineages; this in turn, results in an increase in myeloid cell glycolysis and Glut1 expression. These studies are relevant for the understanding how BM microenvironmental changes can dysregulate B cell development and trigger adaptations in immunometabolism of myeloid cells. My thesis works expands on the potential mechanisms by which VHL in Dmp1-expressing cells regulate the development of distinct hematopoietic cell lineages in the BM, further elucidating and expanding our definition of “immune niches” to include osteocytes, bone, and vasculature.

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