title: Activated Gs signaling in osteoblastic cells alters the hematopoietic stem cell niche in mice.
abstract: Adult hematopoiesis occurs primarily in the BM space where hematopoietic cells interact with stromal niche cells. Despite this close association, little is known about the specific roles of osteoblastic lineage cells (OBCs) in maintaining hematopoietic stem cells (HSCs), and how conditions affecting bone formation influence HSC function. Here we use a transgenic mouse model with the ColI(2.3) promoter driving a ligand-independent, constitutively active 5HT4 serotonin receptor (Rs1) to address how the massive increase in trabecular bone formation resulting from increased G(s) signaling in OBCs impacts HSC function and blood production. Rs1 mice display fibrous dysplasia, BM aplasia, progressive loss of HSC numbers, and impaired megakaryocyte/erythrocyte development with defective recovery after hematopoietic injury. These hematopoietic defects develop without compensatory extramedullary hematopoiesis, and the loss of HSCs occurs despite a paradoxical expansion of stromal niche cells with putative HSC-supportive activity (ie, endothelial, mesenchymal, and osteoblastic cells). However, Rs1-expressing OBCs show decreased expression of key HSC-supportive factors and impaired ability to maintain HSCs. Our findings indicate that long-term activation of G(s) signaling in OBCs leads to contextual changes in the BM niche that adversely affect HSC maintenance and blood homeostasis.
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, USA.
authors.forename: Koen
authors.initials: K
authors.lastname: Schepers
authors.forename: Edward C
authors.initials: EC
authors.lastname: Hsiao
authors.forename: Trit
authors.initials: T
authors.lastname: Garg
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Scott
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Passegué
mesh_terms: D000818:Animals; D015415:Biomarkers; D015519:Bone Density; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication; D002452:Cell Count; D004920:Erythropoiesis / Q000235:genetics; D005260:Female; D005357:Fibrous Dysplasia of Bone / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics / Q000378:metabolism; D012010:Red-Cell Aplasia, Pure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D055153:Stem Cell Niche / Q000235:genetics
chemical_list: D015415:Biomarkers; D044422:Receptors, Serotonin, 5-HT4