title: PTH expands short-term murine hemopoietic stem cells through T cells.
abstract: Intermittent parathyroid hormone (iPTH) treatment expands hemopoietic stem and progenitor cells (HSPCs), but the involved mechanisms and the affected HSPC populations are mostly unknown. Here we show that T cells are required for iPTH to expand short-term HSPCs (ST-HSPCs) and improve blood cell engraftment and host survival after BM transplantation. Silencing of PTH/PTH-related protein receptor (PPR) in T cells abrogates the effects of iPTH, thus demonstrating a requirement for direct PPR signaling in T cells. Mechanistically, iPTH expands ST-HSPCs by activating Wnt signaling in HSPCs and stromal cells (SCs) through T-cell production of the Wnt ligand Wnt10b. Attesting to the relevance of Wnt10b, iPTH fails to expand ST-HSPCs in mice with Wnt10b(-/-) T cells. Moreover, iPTH fails to promote engraftment and survival after BM transplantation in Wnt10b null mice. In summary, direct PPR signaling in T cells and the resulting production of Wnt10b play a pivotal role in the mechanism by which iPTH expands ST-HSPCs. The data suggest that T cells may provide pharmacologic targets for HSPC expansion.
authors.affiliation: Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Jau-Yi
authors.initials: JY
authors.lastname: Li
authors.forename: Jonathan
authors.initials: J
authors.lastname: Adams
authors.forename: Laura M
authors.initials: LM
authors.lastname: Calvi
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Lane
authors.forename: Richard
authors.initials: R
authors.lastname: DiPaolo
authors.forename: M Neale
authors.initials: MN
authors.lastname: Weitzmann
authors.forename: Roberto
authors.initials: R
authors.lastname: Pacifici
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D019674:Genes, T-Cell Receptor beta / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D051153:Wnt Proteins / Q000235:genetics
chemical_list: D010281:Parathyroid Hormone; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse