title: Antifibrotic, Antioxidant, and Immunomodulatory Effects of Mesenchymal Stem Cells in HOCl-Induced Systemic Sclerosis.
abstract: OBJECTIVE
  Systemic sclerosis (SSc) is a rare intractable disease with unmet medical need and fibrosis-related mortality. Absence of efficient treatments has prompted the development of novel therapeutic strategies, among which mesenchymal stem cells/stromal cells (MSCs) or progenitor stromal cells appear to be one of the most attractive options. The purpose of this study was to use the murine model of hypochlorite-induced SSc to investigate the systemic effects of MSCs on the main features of the diffuse form of the disease: skin and lung fibrosis, autoimmunity, and oxidative status.
  
  
  METHODS
  We compared the effects of different doses of MSCs (2.5 × 10(5) , 5 × 10(5) , and 10(6) ) infused at different time points. Skin thickness was assessed during the experiment. At the time of euthanasia, biologic parameters were quantified in blood and tissues (by enzyme-linked immunosorbent assay, quantitative reverse transcription-polymerase chain reaction, assessment of collagen content). Assessments of histology and immunostaining were also performed.
  
  
  RESULTS
  A lower expression of markers of fibrosis (Col1, Col3, Tgfb1, and aSma) was observed in both skin and lung following MSC infusion, which was consistent with histologic improvement and was inversely proportional to the injected dose. Importantly, sera from treated mice exhibited lower levels of anti-Scl-70 autoantibodies and enhanced antioxidant capacity, confirming the systemic effect of MSCs. Of interest, MSC administration was efficient in both the preventive and the curative approach. We further provide evidence that MSCs exerted an antifibrotic role by normalizing extracellular matrix remodeling parameters as well as reducing proinflammatory cytokine levels and increasing antioxidant defenses.
  
  
  CONCLUSIONS
  The results of this study demonstrate the beneficial and systemic effects of MSC administration in the HOCl murine model of diffuse SSc, which is a promising finding from a clinical perspective.
authors.affiliation: INSERM U1183, St. Eloi Hospital, and Montpellier University Medical School, Montpellier, France.
authors.forename: Alexandre T J
authors.initials: AT
authors.lastname: Maria
authors.affiliation: INSERM U1183, St. Eloi Hospital, and Montpellier University Medical School, Montpellier, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Toupet
authors.affiliation: INSERM U1183, St. Eloi Hospital, and Montpellier University Medical School, Montpellier, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Bony
authors.affiliation: INSERM U1194 and UMS BioCampus Montpellier, Montpellier, France.
authors.forename: Nelly
authors.initials: N
authors.lastname: Pirot
authors.affiliation: University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Vozenin
authors.affiliation: University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
authors.forename: Benoît
authors.initials: B
authors.lastname: Petit
authors.affiliation: Montpellier University Medical School, Montpellier, France, and Caremeau Hospital, Nîmes, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Roger
authors.affiliation: Paris Descartes University and EA1833, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
authors.affiliation: St. Eloi Hospital and Montpellier University Medical School, Montpellier, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Le Quellec
authors.affiliation: INSERM U1183, St. Eloi Hospital, Montpellier University Medical School, and Lapeyronie Hospital, Montpellier, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Jorgensen
authors.affiliation: INSERM U1183, St. Eloi Hospital, and Montpellier University Medical School, Montpellier, France.
authors.forename: Danièle
authors.initials: D
authors.lastname: Noël
authors.affiliation: INSERM U1183, St. Eloi Hospital, and Montpellier University Medical School, Montpellier, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Guilpain
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D024042:Collagen Type I / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D004264:DNA Topoisomerases, Type I / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis; D006997:Hypochlorous Acid / Q000633:toxicity; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000276:immunology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045743:Scleroderma, Diffuse / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D059467:Transcriptome; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D001323:Autoantibodies; D024042:Collagen Type I; D024061:Collagen Type III; D016877:Oxidants; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D006997:Hypochlorous Acid; D004264:DNA Topoisomerases, Type I