title: FLVCR is necessary for erythroid maturation, may contribute to platelet maturation, but is dispensable for normal hematopoietic stem cell function.
abstract: Heme is a pleiotropic molecule that is important for oxygen and oxidative metabolism, most notably as the prosthetic group of hemoglobin and cytochromes. Because excess free intracellular heme is toxic, organisms have developed mechanisms to tightly regulate its concentration. One mechanism is through active heme export by the group C feline leukemia virus receptor (FLVCR). Previously, we have shown that FLVCR is necessary for embryonic and postnatal erythropoiesis. However, FLVCR is also expressed in numerous other tissues, including hematopoietic stem cells (HSCs). To explore a possible role for FLVCR in HSC function, we performed serial, competitive repopulation transplant experiments using FLVCR-deleted and control bone marrow cells, along with wild-type competitor cells. Loss of FLVCR did not impact HSC function under steady-state or myelotoxic stress conditions (such as arsenic or radiation exposure), nor did FLVCR deletion result in alterations in the various progenitor compartments. However, even when 95% of the donor bone marrow cells lacked FLVCR, all red cells in recipient mice were wild type. This is due to the increased apoptosis of FLVCR-deleted proerythroblasts. Also, remarkably, loss of FLVCR increased megakaryocyte ploidy. Together, these findings show FLVCR is redundant in stem cells but has critical and contrasting stage-specific roles in discrete hematopoietic lineages.
authors.affiliation: Division of Hematology, Department of Medicine, University of Washington, Seattle, WA.
authors.forename: John C H
authors.initials: JC
authors.lastname: Byon
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Doty
authors.forename: Janis L
authors.initials: JL
authors.lastname: Abkowitz
mesh_terms: D000818:Animals; D017209:Apoptosis; D001792:Blood Platelets / Q000166:cytology*; D019070:Cell Lineage; D004900:Erythroblasts / Q000166:cytology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006418:Heme / Q000737:chemistry; D008533:Megakaryocytes / Q000166:cytology; D026901:Membrane Transport Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress; D011991:Receptors, Virus / Q000502:physiology*
chemical_list: C526650:Flvcr1 protein, mouse; D026901:Membrane Transport Proteins; D011991:Receptors, Virus; D006418:Heme
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