title: Interruption of CD40 Pathway Improves Efficacy of Transplanted Endothelial Progenitor Cells in Monocrotaline Induced Pulmonary Arterial Hypertension.
abstract: OBJECTIVE
  Transplantation of endothelial progenitor cells (EPCs) plays a therapeutic role in pulmonary arterial hypertension (PAH). Meanwhile, recruitment of progenitors has potential inflammatory effects and exaggerates vascular injury. CD40 pathway is identified as a major player in vascular inflammatory events. In this study, we investigated the role of CD40 pathway in regulating early outgrowth EPC functions, and searched for improvements in PAH cell therapy.
  
  
  METHODS
  EPCs were isolated from rat bone marrow and cultured for 7 days. After treatment with soluble CD40 ligand (sCD40L) for 24 hours, EPC migration, adhesion, proliferation, paracrine and vasculogenesis functions were tested. Rat PAH model was founded by subcutaneous injection of monocrotaline (MCT). Control EPCs or lentivirus vectors (Lv)-shRNA-CD40 EPCs were infused via tail vein at day 7, 14, and 21 after MCT injection. Therapeutic effects were evaluated at day 28.
  
  
  RESULTS
  sCD40L dose-dependently impaired EPC migration, adhesion, proliferation, and vasculogenesis functions. However, paracrine effects of soluble intercellular adhesion molecule-1, vascular endothelial growth factor and interleukin-6 were dose-dependently improved by sCD40L. Control EPC-derived conditioned medium protected endothelial cell in vitro vasculogenesis, while sCD40L-pretreated ones showed detrimental effects. After MCT injection, sCD40L levels in rat serum increased gradually. Other than in vitro results, benefits of both two EPC treatments were obvious, even taken at day 21. Benefits of control EPCs wore off over time, but those of Lv-shRNA-CD40 EPCs were more effective and enduring, as characterized by both ameliorated rat hemodynamic and reversed vascular remodeling. Furthermore, Lv-shRNA-CD40 EPCs integrated into endothelium better, rather than into adventitia and media.
  
  
  CONCLUSIONS
  sCD40L impaired protective effects of EPCs. Traditional EPC treatments were limited in PAH, while interruption of CD40 pathway of transplanted cells could apparently improve the therapeutic efficacy.
authors.forename: Pan
authors.initials: P
authors.lastname: YanYun
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.forename: JinXiu
authors.initials: J
authors.lastname: Yang
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.forename: ZeWei
authors.initials: Z
authors.lastname: Sun
authors.forename: LiFang
authors.initials: L
authors.lastname: Ye
authors.forename: JianHua
authors.initials: J
authors.lastname: Zhu
authors.forename: XingXiang
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000276:immunology / Q000628:therapy*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D008297:Male; D016686:Monocrotaline; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D033581:Stem Cell Transplantation / Q000379:methods; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand; D016686:Monocrotaline