title: Lentiviral transduction of apoAI into hematopoietic progenitor cells and macrophages: applications to cell therapy of atherosclerosis.
abstract: OBJECTIVE
  We used genetically engineered mouse hematopoietic progenitor cells (HPCs) to investigate the therapeutic effects of human apoAI on atherosclerosis in apoE(-/-) mice.
  
  
  RESULTS
  Lentiviral constructs expressing either human apoAI (LV-apoAI) or green fluorescent protein (LV-GFP) cDNA under a macrophage specific promoter (CD68) were generated and used for ex vivo transduction of mouse HPCs and macrophages. The transduction efficiency was >25% for HPCs and >70% for macrophages. ApoAI was found in the macrophage culture media, mostly associated with the HDL fraction. Interestingly, a significant increase in mRNA and protein levels for ATP binding cassette A1 (ABCA1) and ABCG1 were found in apoAI-expressing macrophages after acLDL loading. Expression of apoAI significantly increased cholesterol efflux in wild-type and apoE(-/-) macrophages. HPCs transduced with LV-apoAI ex vivo and then transplanted into apoE(-/-) mice caused a 50% reduction in atherosclerotic lesion area compared to GFP controls, without influencing plasma HDL-C levels.
  
  
  CONCLUSIONS
  Lentiviral transduction of apoAI into HPCs reduces atherosclerosis in apoE(-/-) mice. Expression of apoAI in macrophages improves cholesterol trafficking in wild-type apoE-producing macrophages and causes upregulation of ABCA1 and ABCG1. These novel observations set the stage for a cell therapy approach to atherosclerosis regression, exploiting the cooperation between apoE and apoAI to maximize cholesterol exit from the plaque.
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville TN 37232-6300, USA. yan.ru.su@vanderbilt.edu
authors.forename: Yan Ru
authors.initials: YR
authors.lastname: Su
authors.forename: John L
authors.initials: JL
authors.lastname: Blakemore
authors.forename: Youmin
authors.initials: Y
authors.lastname: Zhang
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D016086:Lentivirus; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051381:Rats; D014161:Transduction, Genetic / Q000379:methods
chemical_list: D016632:Apolipoprotein A-I