ATP-Binding Cassette Transporters and HDL Suppress Hematopoietic Stem Cell Proliferation

By L. Yvan-Charvet, T. Pagler, E. Gautier, S. Avagyan, Read L. Siry, Seongah Han, C. Welch, Nan Wang, G. Randolph, H. Snoeck and 1 more. Science, 2010

734 citations recorded by the source corpus.

Inhibiting Leukocytosis Leukocytosis—an elevated white blood cell count—contributes by unknown mechanisms to the pathogenesis of atherosclerosis and associated coronary heart disease. Now, Yvan-Charvet et al. (p. 1689, published online 20 May; see the Perspective by Hansson and Björkholm) show that the adenosine triphosphate–binding cassette transporters ABCA1 and ABCG1 are critical suppressors of atherosclerosis-associated leukocytosis. Mice deficient in both transporters in blood-producing hematopoietic cells possessed increased levels of hematopoietic stem and multipotential progenitor cells and accelerated atherosclerosis. ABCA1 and ABGA1 protect against atherosclerosis by promoting cholesterol efflux from cholesterol-laden macrophage foam cells to lipid-poor high-density lipoprotein (HDL) and apolipoprotein A-1. The leukocytosis and atherosclerosis in ABCA1- and ABG1-deficient mice were reversed in the presence of high amounts of HDL. Thus, signaling already known to inhibit atherosclerosis by reducing cholesterol in atherosclerotic plaques also reduces atherosclerosis-associated leukocytosis. Pathways that reduce cholesterol in atherosclerosis also suppress increased immune cell numbers associated with the disease. 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.

Subfields: Immunology, Physiology, Surgery

View Paper: https://www.semanticscholar.org/paper/5a64106ccebce21f857c331b2e302ee0b77af1c4

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Citations in the corpus

The spleen in local and systemic regulation of immunity (2013, background): “, 2011), and (3) suppress splenic myelopoieisis (Yvan-Charvet et al., 2010; Murphy et al., 2011).”
Atherosclerosis: current pathogenesis and therapeutic options (2011, background): “82 ) can enhance cholesterol-rich raft formation in hematopoietic stem cells, increasing surface expression of the common IL-3 and GM-CSF receptor β-subunit, which, in turn, increases IL-3– and GM-CSF–triggered downstream signaling and myeloproliferatio”
Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming (2018, background): “…have linked hypercholesterolemia to reprogramming of hematopoietic stem cells (Murphy et al., 2011; Seijkens et al., 2014; van Kampen et al., 2014; Yvan-Charvet et al., 2010), we performed functional and transcriptional analyses of GMPs, the proximate precursors of circulating myeloid subsets.”
Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity (2018, background): “In this regard, alterations in the cholesterol composition of the membrane can influence the localization and signaling capacity of CD131 (Kaul et al., 2016; Yvan-Charvet et al., 2010).”
Impact of Obesity and Metabolic Syndrome on Immunity. (2016, background): “Thymus characteristics C56BL/6 mice fed HFD [ Thymic involution and adiposity (18) Diabetic rats, streptozotocin-induced [ Thymic involution (41) Diabetic mice, alloxan-induced [ Thymic involution (42) Leptin deficiency (ob/ob mice) Y Thymus size and cellularity, [ thymocyte apoptosis (43) Spleen ch”
Expression of Linear and Novel Circular Forms of an INK4/ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk (2010, background): “Most recently, excess proliferation of hematopoietic progenitor cells, which is in part controlled by p16 expression during aging [24], has been associated with atherosclerosis in a murine model [25].”
The Cellular Biology of Macrophages in Atherosclerosis (2011, positive): “…efferocytosis, including oxidative stress-induced efferocyte death resulting from defective cholesterol efflux after apoptotic cell engulfment (Yvan-Charvet et al., 2010b); LP-associated hydrolysis of oxidized phosphatidylserine on the surface of apoptotic cells by phospholipase A2 (PLA2),…”
Monocyte-Macrophages and T Cells in Atherosclerosis (2017, positive): “The net effect of increases in T cell cholesterol on lesion development and inflammation are likely to reflect changes in the Teff-Treg balance and the influence of Teff cells on lesional macrophages. keyHSPC growth factors, IL-3 andGM-CSF (Yvan-Charvet et al., 2010).”