title: Regulation of hematopoietic stem and progenitor cell mobilization by cholesterol efflux pathways.
abstract: Intact cholesterol homeostasis helps to maintain hematopoietic stem and multipotential progenitor cell (HSPC) quiescence. Mice with defects in cholesterol efflux pathways due to deficiencies of the ATP binding cassette transporters ABCA1 and ABCG1 displayed a dramatic increase in HSPC mobilization and extramedullary hematopoiesis. Increased extramedullary hematopoiesis was associated with elevated serum levels of G-CSF due to generation of IL-23 by splenic macrophages and dendritic cells. This favored hematopoietic lineage decisions toward granulocytes rather than macrophages in the bone marrow leading to impaired support for osteoblasts and decreased Cxcl12/SDF-1 production by mesenchymal progenitors. Greater HSPC mobilization and extramedullary hematopoiesis were reversed by raising HDL levels in Abca1(-/-)Abcg1(-/-) and Apoe(-/-) mice or in a mouse model of myeloproliferative neoplasm mediated by Flt3-ITD mutation. Our data identify a role of cholesterol efflux pathways in the control of HSPC mobilization. This may translate into therapeutic strategies for atherosclerosis and hematologic malignancies.
authors.affiliation: Department of Medicine, Division of Molecular Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Marit
authors.initials: M
authors.lastname: Westerterp
authors.forename: Samuel
authors.initials: S
authors.lastname: Gourion-Arsiquaud
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: Alan
authors.initials: A
authors.lastname: Shih
authors.forename: Serge
authors.initials: S
authors.lastname: Cremers
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
authors.forename: Laurent
authors.initials: L
authors.lastname: Yvan-Charvet
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D002465:Cell Movement; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: C577836:ABCA1 protein, human; C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008074:Lipoproteins; D002784:Cholesterol