title: FSP-1 silencing in bone marrow cells suppresses neointima formation in vein graft.
abstract: BACKGROUND
  Fibroblast-specific protein 1 (FSP-1) plays multiple roles in promoting cell proliferation and motility. Increased FSP-1 expression in smooth muscle cells (SMCs) has been associated with their enhanced proliferation.
  
  
  OBJECTIVE
  To study how FSP-1 contributes to neointima formation of vein grafts.
  
  
  METHODS
  Arteriovenous grafts were created in wild-type or FSP-1-GFP mice (green fluorescent protein expression regulated by FSP-1 promoter). The effects of FSP-1 on bone marrow (BM) cell migration and on SMC proliferation were studied in vivo and in vitro.
  
  
  RESULTS
  On creation of a vein graft, there was rapid deposition of platelets on the denuded surface leading to secretion of the chemokine stromal cell-derived factor-1α (SDF-1α). This was followed by recruitment of BM-derived cells expressing the SDF-1α receptor CXCR4; homing of FSP-1-positive cells was found to be dependent on platelet-derived SDF-1α. FSP-1 was expressed in 8% of the BM cells, and 20% of these express CD45; 85% of FSP-1-positive cells express CD11b. We found that the FSP-1-positive cells migrated into the vein graft in a Rac-1-dependent fashion. FSP-1 expression was also found to stimulate proliferation of SMCs through a MEK5-ERK5 signaling pathway that can be suppressed by a dominant-negative Rac1. Consequently, knocking down FSP-1 expression in BM cells prevented neointimal formation.
  
  
  CONCLUSIONS
  BM-derived FSP-1(+) cells enhance neointima formation through an increase in transendothelial invasion with stimulation of SMC proliferation. The Rac1 and ERK5 signaling cascade mediate FSP-1-induced responses in SMCs and BM cells. This novel pathophysiology suggests a new therapeutic target, FSP-1, for preventing the development of neointima in vein grafts.
authors: Nephrology Division, Baylor College of Medicine, Houston, TX 77030, USA. jizhongc@bcm.edu
authors: Jizhong
authors: J
authors: Cheng
authors: Yun
authors: Y
authors: Wang
authors: Anlin
authors: A
authors: Liang
authors: Lixin
authors: L
authors: Jia
authors: Jie
authors: J
authors: Du
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D018920:Coculture Techniques; D015316:Genetic Therapy; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D018836:Inflammation Mediators / Q000378:metabolism; D048671:MAP Kinase Kinase 5 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D057705:Transendothelial and Transepithelial Migration; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D058017:Vascular Grafting; D014682:Vena Cava, Inferior / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D018836:Inflammation Mediators; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D011993:Recombinant Fusion Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D049452:Green Fluorescent Proteins; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein