title: Hematopoietic stem/progenitor cell proliferation and differentiation is differentially regulated by high-density and low-density lipoproteins in mice.
abstract: BACKGROUND
  Hematopoietic stem/progenitor cells (HSPC) are responsible for maintaining the blood system as a result of their self-renewal and multilineage differentiation capacity. Recently, studies have suggested that HDL cholesterol may inhibit and impaired cholesterol efflux may increase HSPC proliferation and differentiation.
  
  
  OBJECTIVE
  We hypothesized that LDL may enhance HSPC proliferation and differentiation while HDL might have the opposing effect which might influence the size of the pool of inflammatory cells.
  
  
  RESULTS
  HSPC number and function were studied in hypercholesterolemic LDL receptor knockout (LDLr(-/-)) mice on high fat diet. Hypercholesterolemia was associated with increased frequency of HSPC, monocytes and granulocytes in the peripheral blood (PB). In addition, an increased proportion of BM HSPC was in G(2)M of the cell cycle, and the percentage of HSPC and granulocyte-macrophage progenitors (GMP) increased in BM of LDLr(-/-) mice. When BM Lin-Sca-1+cKit+ (i.e. "LSK") cells were cultured in the presence of LDL in vitro we also found enhanced differentiation towards monocytes and granulocytes. Furthermore, LDL promoted lineage negative (Lin-) cells motility. The modulation by LDL on HSPC differentiation into granulocytes and motility was inhibited by inhibiting ERK phosphorylation. By contrast, when mice were infused with human apoA-I (the major apolipoprotein of HDL) or reconstituted HDL (rHDL), the frequency and proliferation of HSPC was reduced in BM in vivo. HDL also reversed the LDL-induced monocyte and granulocyte differentiation in vitro.
  
  
  CONCLUSIONS
  Our data suggest that LDL and HDL have opposing effects on HSPC proliferation and differentiation. It will be of interest to determine if breakdown of HSPC homeostasis by hypercholesterolemia contributes to inflammation and atherosclerosis progression.
authors.affiliation: Interdepartementaal Stem Cell Institute, Katholieke Universiteit Leuven, Belgium. yingmei.feng@med.kuleuven.be
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Feng
authors.forename: Sarah
authors.initials: S
authors.lastname: Schouteden
authors.forename: Rachel
authors.initials: R
authors.lastname: Geenens
authors.forename: Vik
authors.initials: V
authors.lastname: Van Duppen
authors.forename: Paul
authors.initials: P
authors.lastname: Herijgers
authors.forename: Paul
authors.initials: P
authors.lastname: Holvoet
authors.forename: Paul P
authors.initials: PP
authors.lastname: Van Veldhoven
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Verfaillie
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055786:Gene Knockout Techniques; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics / Q000378:metabolism; D007964:Leukocytosis / Q000209:etiology; D008075:Lipoproteins, HDL / Q000008:administration & dosage / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
chemical_list: D016632:Apolipoprotein A-I; D018955:CD36 Antigens; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D048049:Extracellular Signal-Regulated MAP Kinases