ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation.
Elevated leukocyte cell numbers (leukocytosis), and monocytes in particular, promote atherosclerosis; however, how they become increased is poorly understood. Mice deficient in the adenosine triphosphate-binding cassette (ABC) transporters ABCA1 and ABCG1, which promote cholesterol efflux from macrophages and suppress atherosclerosis in hypercholesterolemic mice, displayed leukocytosis, a transplantable myeloproliferative disorder, and a dramatic expansion of the stem and progenitor cell population containing Lin(-)Sca-1(+)Kit+ (LSK) in the bone marrow. Transplantation of Abca1(-/-) Abcg1(-/-) bone marrow into apolipoprotein A-1 transgenic mice with elevated levels of high-density lipoprotein (HDL) suppressed the LSK population, reduced leukocytosis, reversed the myeloproliferative disorder, and accelerated atherosclerosis. The findings indicate that ABCA1, ABCG1, and HDL inhibit the proliferation of hematopoietic stem and multipotential progenitor cells and connect expansion of these populations with leukocytosis and accelerated atherosclerosis.
Yvan-Charvet
Laurent
L
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA. ly2159@columbia.edu
Pagler
Tamara
T
Gautier
Emmanuel L
EL
Avagyan
Serine
S
Siry
Read L
RL
Han
Seongah
S
Welch
Carrie L
CL
Wang
Nan
N
Randolph
Gwendalyn J
GJ
Snoeck
Hans W
HW
Tall
Alan R
AR
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006937:Hypercholesterolemia / Q000378:metabolism; D007964:Leukocytosis / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000502:physiology; D023461:Myeloid Progenitor Cells / Q000502:physiology*; D009196:Myeloproliferative Disorders / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D010641:Phenotype; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D016185:Receptors, Interleukin-3 / Q000378:metabolism; D015398:Signal Transduction
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; D008075:Lipoproteins, HDL; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016185:Receptors, Interleukin-3; D002784:Cholesterol