title: Toll-like receptor 3 regulates cord blood-derived endothelial cell function in vitro and in vivo.
abstract: Circulating endothelial progenitor cells (cEPC) are capable of homing to neovascularisation sites, in which they proliferate and differentiate into endothelial cells. Transplantation of cEPC-derived cells, in particular those isolated from umbilical cord blood (UCB), has emerged as a promising approach in the treatment of cardio-vascular diseases. After in vivo transplantation, these cells may be exposed to local or systemic inflammation or pathogens, of which they are a common target. Because Toll-like receptors (TLR) are critical in detecting pathogens and in initiating inflammatory responses, we hypothesized that TLR may govern UCB cEPC-derived cells function. While these cells expressed almost all TLR, we found that only TLR3 dramatically impaired cell properties. TLR3 activation inhibited cell proliferation, modified cell cycle entry, impaired the in vitro angiogenic properties and induced pro-inflammatory cytokines production. The anti-angiogenic effect of TLR3 activation was confirmed in vivo in a hind-limb ischemic mice model. Moreover, TLR3 activation consistently leads to an upregulation of miR-29b, -146a and -155 and to a deregulation of cytoskeleton and cell cycle regulator. Hence, TLR3 activation is likely to be a key regulator of cEPC-derived cells properties.
authors.affiliation: AP-HP, Unité de Thérapie Cellulaire et CIC de Biothérapies, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, 75475, Paris Cedex 10, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Grelier
authors.forename: Audrey
authors.initials: A
authors.lastname: Cras
authors.forename: Nicole
authors.initials: N
authors.lastname: Balitrand
authors.forename: Catherine
authors.initials: C
authors.lastname: Delmau
authors.forename: Séverine
authors.initials: S
authors.lastname: Lecourt
authors.forename: Yves
authors.initials: Y
authors.lastname: Lepelletier
authors.forename: Hélène
authors.initials: H
authors.lastname: Riesterer
authors.forename: Delphine
authors.initials: D
authors.lastname: Freida
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lataillade
authors.forename: Marie-Caroline
authors.initials: MC
authors.lastname: Lebousse-Kerdiles
authors.forename: Wendy
authors.initials: W
authors.lastname: Cuccini
authors.forename: Regis
authors.initials: R
authors.lastname: Peffault de Latour
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marolleau
authors.forename: Georges
authors.initials: G
authors.lastname: Uzan
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.forename: Valérie
authors.initials: V
authors.lastname: Vanneaux
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D005786:Gene Expression Regulation / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007231:Infant, Newborn; D007511:Ischemia / Q000601:surgery; D008024:Ligands; D008077:Lipoproteins, LDL / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009841:Oligonucleotides / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000096:biosynthesis / Q000502:physiology*; D051193:Toll-Like Receptors / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014945:Wound Healing
chemical_list: D016207:Cytokines; D008024:Ligands; D008077:Lipoproteins, LDL; D035683:MicroRNAs; D009841:Oligonucleotides; C495344:TLR3 protein, human; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C032629:acetyl-LDL; D011070:Poly I-C