title: Adventitial stem cells in vein grafts display multilineage potential that contributes to neointimal formation.
abstract: OBJECTIVE
  This study was designed to carry out the characterization of stem cells within the adventitia and to elucidate their functional role in the pathogenesis of vein graft atherosclerosis.
  
  
  RESULTS
  A mouse vein graft model was used to investigate the functional role of adventitial stem/progenitor cells on atherosclerosis. The adventitia of vein grafts underwent significant remodeling during early stages of vessel grafting and displayed markedly heterogeneous cell compositions. Immunofluorescence staining indicated a significant number of stem cell antigen-1-positive cells that were closely located to vasa vasorum. In vitro clonogenic assays demonstrated 1% to 11% of growing rates from adventitial cell cultures, most of which could be differentiated into smooth muscle cells (SMCs). These stem cell antigen-1-positive cells also displayed a potential to differentiate into adipogenic, osteogenic, or chondrogenic lineages in vitro. In light of the proatherogenic roles of SMCs in atherosclerosis, we focused on the functional roles of progenitor-SMC differentiation, in which we subsequently demonstrated that it was driven by direct interaction of the integrin/collagen IV axis. The ex vivo bioreactor system revealed the migratory capacity of stem cell antigen-1-positive progenitor cells into the vessel wall in response to stromal cell-derived factor-1. Stem cell antigen-1-positive cells that were applied to the outer layer of vein grafts showed enhanced atherosclerosis in apolipoprotein E-deficient mice, which contributed to ≈ 30% of neointimal SMCs.
  
  
  CONCLUSIONS
  We demonstrate that during pathological conditions in vein grafting, the adventitia harbors stem/progenitor cells that can actively participate in the pathogenesis of vascular disease via differentiation into SMCs.
authors.affiliation: Department of Vascular Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Yikuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Mei Mei
authors.initials: MM
authors.lastname: Wong
authors.forename: Paola
authors.initials: P
authors.lastname: Campagnolo
authors.forename: Russell
authors.initials: R
authors.lastname: Simpson
authors.forename: Bernhard
authors.initials: B
authors.lastname: Winkler
authors.forename: Andriani
authors.initials: A
authors.lastname: Margariti
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Hu
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
mesh_terms: D063194:Adventitia / Q000473:pathology; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology*; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D004195:Disease Models, Animal; D006083:Graft Occlusion, Vascular / Q000473:pathology*; D016023:Integrins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D058426:Neointima / Q000473:pathology*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D014182:Transplantation, Autologous; D014680:Veins / Q000473:pathology / Q000637:transplantation*
chemical_list: D000950:Antigens, Ly; D001057:Apolipoproteins E; D024141:Collagen Type IV; D016023:Integrins; C074650:Ly6a protein, mouse; D008565:Membrane Proteins
keywords: adventitial tissue; atherosclerosis; cell movement; smooth muscle cells; stem cells