title: Evidence that the expression of transferrin receptor 1 on erythroid marrow cells mediates hepcidin suppression in the liver.
abstract: Hepcidin is the key regulator of iron absorption and recycling, and its expression is suppressed by red blood cell production. When erythropoiesis is expanded, hepcidin expression decreases. To gain insight into the stage of erythroid differentiation at which the regulation might originate, we measured serum hepcidin levels in archived pure red cell aplasia samples from patients whose block in erythroid differentiation was well defined by hematopoietic colony assays and marrow morphologic review. Hepcidin values are high or high normal in pure red cell aplasia patients in whom erythropoiesis is inhibited prior to the proerythroblast stage, but are suppressed in patients with excess proerythroblasts and few later erythroid cells. These data suggest that the suppressive effect of erythropoietic activity on hepcidin expression can arise from proerythroblasts, the stage at which transferrin receptor 1 expression peaks, prompting the hypothesis that transferrin receptor 1 expression on erythroid precursors is a proximal mediator of the erythroid regulator of hepcidin expression. Our characterization of erythropoiesis, iron status, and hepcidin expression in mice with global or hematopoietic cell-specific haploinsufficiency of transferrin receptor 1 provides initial supporting data for this model. The regulation appears independent of erythroferrone and growth differentiation factor 15, supporting the concept that several mechanisms signal iron need in response to an expanded erythron.
authors.affiliation: Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Siobán B
authors.initials: SB
authors.lastname: Keel
authors.affiliation: Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Doty
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Nemeth
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Sindhu
authors.initials: S
authors.lastname: Cherian
authors.affiliation: Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Ganz
authors.affiliation: Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington, USA. Electronic address: janabk@u.washington.edu.
authors.forename: Janis L
authors.initials: JL
authors.lastname: Abkowitz
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D064451:Hepcidins / Q000037:antagonists & inhibitors*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D011990:Receptors, Transferrin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D064451:Hepcidins; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse