title: PPARβ/δ directs the therapeutic potential of mesenchymal stem cells in arthritis.
abstract: OBJECTIVE
  To define how peroxisome proliferator-activated receptor (PPAR) β/δ expression level in mesenchymal stem cells (MSCs) could predict and direct both their immunosuppressive and therapeutic properties. PPARβ/δ interacts with factors such as nuclear factor-kappa B (NF-κB) and regulates the expression of molecules including vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1. Since these molecules are critical for MSC function, we investigated the role of PPARβ/δ on MSC immunosuppressive properties.
  
  
  METHODS
  We either treated human MSCs (hMSCs) with the irreversible PPARβ/δ antagonist (GSK3787) or derived MSCs from mice deficient for PPARβ/δ (PPARβ/δ-/-MSCs). We used the collagen-induced arthritis (CIA) as model of immune-mediated disorder and the MSC-immune cell coculture assays.
  
  
  RESULTS
  Modulation of PPARβ/δ expression in hMSCs either using GSK3787 or hMSCs from different origin reveals that MSC immunosuppressive potential is inversely correlated with Ppard expression. This was consistent with the higher capacity of PPARβ/δ-/-MSCs to inhibit both the proliferation of T lymphocytes, in vitro, and arthritic development and progression in CIA compared with PPARβ/δ+/+MSCs. When primed with proinflammatory cytokines to exhibit an immunoregulatory phenotype, PPARβ/δ-/-MSCs expressed a higher level of mediators of MSC immunosuppression including VCAM-1, ICAM-1 and nitric oxide (NO) than PPARβ/δ+/+MSCs. The enhanced NO2production by PPARβ/δ-/-MSCs was due to the increased retention of NF-κB p65 subunit on the κB elements of the inducible nitric oxide synthase promoter resulting from PPARβ/δ silencing.
  
  
  CONCLUSIONS
  Our study is the first to show that the inhibition or knockdown of PPARβ/δ in MSCs primes their immunoregulatory functions. Thus, the regulation of PPARβ/δ expression provides a new strategy to generate therapeutic MSCs with a stable regulatory phenotype.
authors.affiliation: Inserm U1183, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: P
authors.initials: P
authors.lastname: Luz-Crawford
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Ipseiz
authors.affiliation: Inserm U1183, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: G
authors.initials: G
authors.lastname: Espinosa-Carrasco
authors.affiliation: Inserm U1183, Montpellier, France.|Université Montpellier, Montpellier, France.|Universidad San Francisco de Quito USFQ, Colegio de Ciencias de la Salud, Escuela de Medicina, Hospital de los Valles, Quito Ecuador.
authors.forename: A
authors.initials: A
authors.lastname: Caicedo
authors.affiliation: Inserm U1183, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: G
authors.initials: G
authors.lastname: Tejedor
authors.affiliation: Inserm U1183, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: K
authors.initials: K
authors.lastname: Toupet
authors.affiliation: Inserm U1183, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: J
authors.initials: J
authors.lastname: Loriau
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Scholtysek
authors.affiliation: Universidad San Francisco de Quito USFQ, Colegio de Ciencias de la Salud, Escuela de Medicina, Hospital de los Valles, Quito Ecuador.
authors.forename: C
authors.initials: C
authors.lastname: Stoll
authors.affiliation: Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, Santiago, Chile.
authors.forename: M
authors.initials: M
authors.lastname: Khoury
authors.affiliation: Inserm U1183, Montpellier, France.|Université Montpellier, Montpellier, France.|Service d'Immuno-Rhumatologie Thérapeutique, Hôpital Lapeyronie, Montpellier, France.
authors.forename: D
authors.initials: D
authors.lastname: Noël
authors.affiliation: Inserm U1183, Montpellier, France.|Université Montpellier, Montpellier, France.|Service d'Immuno-Rhumatologie Thérapeutique, Hôpital Lapeyronie, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Jorgensen
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Krönke
authors.affiliation: Inserm U1183, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: F
authors.initials: F
authors.lastname: Djouad
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism*; D048068:PPAR-beta / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D016207:Cytokines; D047494:PPAR delta; D048068:PPAR-beta; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase
keywords: Arthritis; Autoimmune Diseases; Treatment