Vhl deficiency in Dmp1-expressing cells affects myeloid development and erythropoiesis: possible effects on myeloerythroid metabolism

Abstract

Abstract The specific types of bone marrow (BM) stromal cells and local BM microenvironments that contribute to the regulation of myelopoiesis are not fully understood. The von-Hippel Lindau protein (VHL) controls responses to hypoxia and could regulate immune metabolism. We investigated this in Dmp1-Cre; Vhl conditional knockout mice (cKO), where Vhl is deleted in mesenchymal stem cells, osteoblasts (OBs) and osteocytes. Similar to previous findings when Vhl is deleted in OBs, we observed low blood glucose levels in the cKO mice, which may reflect an increase in OB cellular glycolysis and increased glucose uptake in the bone. Erythropoietin (Epo) treatment in vivo reduced blood glucose levels in rats. In preliminary studies, 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 hypothesize 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 results in elevated EpoR signaling in myeloid progenitors and lineages; this in turn, results in an increase in myeloid cell glycolysis and Glut1 expression and proliferation. These studies are relevant for the understanding how BM microenvironmental changes can trigger adaptations in immunometabolism of myeloid cells. Supported by grants from NIH (R15 AI154245-01, F31 AI154815), and University of California, Merced