title: Mesenchymal stem cells as active prohealing and immunosuppressive agents in periapical environment: evidence from human and experimental periapical lesions.
abstract: BACKGROUND
  Previous studies describe contrasting molecular profiles of active and inactive periapical granulomas characterized by distinct expression of cytokines, osteoclastogenic factors, and wound healing markers. Although the molecular mechanisms underlying such a dichotomy remain unknown, in this study we investigated the potential involvement of mesenchymal stem cells (MSCs) in determining human and murine periapical lesion activity and outcomes.
  
  
  METHODS
  Periapical granulomas (n = 83) and control samples (n = 24) were comparatively assessed for the expression levels of 11 mesenchymal stem cell (MSC) markers using real-time polymerase chain reaction. Experimental periapical lesions induced in mice were evaluated for MSC marker expression and the effects of AMD3100 treatment on lesion outcomes.
  
  
  RESULTS
  MCS marker expression was prevalent in periapical granulomas compared with that in controls, whereas CD29, CD73, CD90, CD146, CD166, NANOG, Stro-1, and CXCR4 expressions were higher in inactive than in active lesions. Experimental periapical lesion inactivity was also associated with an increased expression of MSC markers. The inhibition of MSC mobilization to the periapex by AMD3100 resulted in increased lesion sizes; decreased expression of MSCs and wound healing markers; and increased expression of interleukin 1 beta (IL-17β), interleukin 17 (IL-17), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and nuclear factor kappa-B ligand (RANKL).
  
  
  CONCLUSIONS
  Our results show that MSC markers are overexpressed in inactive human and experimental periapical lesions and that MSC mobilization results in the attenuation of experimental lesion progression associated with immunosuppressive and prohealing mechanisms.
authors.affiliation: Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo (FOB/USP), Bauru, São Paulo, Brazil.
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Araujo-Pires
authors.affiliation: Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo (FOB/USP), Bauru, São Paulo, Brazil.
authors.forename: Claudia Cristina
authors.initials: CC
authors.lastname: Biguetti
authors.affiliation: Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo (FOB/USP), Bauru, São Paulo, Brazil.
authors.forename: Carlos Eduardo
authors.initials: CE
authors.lastname: Repeke
authors.affiliation: Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo (FOB/USP), Bauru, São Paulo, Brazil.
authors.forename: Camila de Oliveira
authors.initials: Cde O
authors.lastname: Rodini
authors.affiliation: Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo (FOB/USP), Bauru, São Paulo, Brazil.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Campanelli
authors.affiliation: Universidade do Sagrado Coração, Bauru, São Paulo, Brazil.
authors.forename: Ana Paula Favaro
authors.initials: AP
authors.lastname: Trombone
authors.affiliation: Department of Endodontics, School of Dentistry, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Ariadne
authors.initials: A
authors.lastname: Letra
authors.affiliation: Department of Endodontics, School of Dentistry, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Renato Menezes
authors.initials: RM
authors.lastname: Silva
authors.affiliation: Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo (FOB/USP), Bauru, São Paulo, Brazil. Electronic address: garletgp@usp.br.
authors.forename: Gustavo Pompermaier
authors.initials: GP
authors.lastname: Garlet
mesh_terms: D015720:5'-Nucleotidase / Q000032:analysis; D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000032:analysis; D000328:Adult; D000818:Animals; D000954:Antigens, Surface / Q000032:analysis; D001596:Benzylamines; D015415:Biomarkers / Q000032:analysis; D051929:CD146 Antigen / Q000032:analysis; D000080027:Cyclams; D004195:Disease Models, Animal; D006571:Heterocyclic Compounds / Q000627:therapeutic use; D018398:Homeodomain Proteins / Q000032:analysis; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019012:Integrin beta1 / Q000032:analysis; D007371:Interferon-gamma / Q000032:analysis; D020381:Interleukin-17 / Q000032:analysis; D053583:Interleukin-1beta / Q000032:analysis; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008875:Middle Aged; D010484:Periapical Granuloma / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D010486:Periapical Tissue / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D053245:RANK Ligand / Q000032:analysis; D019718:Receptors, CXCR4 / Q000032:analysis / Q000037:antagonists & inhibitors; D018800:Thy-1 Antigens / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014945:Wound Healing / Q000502:physiology
chemical_list: D020410:Activated-Leukocyte Cell Adhesion Molecule; D000954:Antigens, Surface; D001596:Benzylamines; D015415:Biomarkers; D051929:CD146 Antigen; D000080027:Cyclams; D006571:Heterocyclic Compounds; D018398:Homeodomain Proteins; D007166:Immunosuppressive Agents; D019012:Integrin beta1; D020381:Interleukin-17; D053583:Interleukin-1beta; D053245:RANK Ligand; D019718:Receptors, CXCR4; D018800:Thy-1 Antigens; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D015720:5'-Nucleotidase; C088327:plerixafor
keywords: Apical periodontitis; gene expression; mesenchymal stem cells; wound healing