title: Adipose-derived mesenchymal stromal cells modulate tendon fibroblast responses to macrophage-induced inflammation in vitro.
abstract: BACKGROUND
  Macrophage-driven inflammation is a key feature of the early period following tendon repair, but excessive inflammation has been associated with poor clinical outcomes. Modulation of the inflammatory environment using molecular or cellular treatments may provide a means to enhance tendon healing.
  
  
  METHODS
  To examine the effect of pro-inflammatory cytokines secreted by macrophages on tendon fibroblasts (TF), we established in vitro models of cytokine and macrophage-induced inflammation. Gene expression, protein expression, and cell viability assays were used to examine TF responses. In an effort to reduce the negative effects of inflammatory cytokines on TFs, adipose-derived mesenchymal stromal cells (ASCs) were incorporated into the model and their ability to modulate inflammation was investigated.
  
  
  RESULTS
  The inflammatory cytokine interleukin 1 beta (IL-1β) and macrophages of varying phenotypes induced up-regulation of pro-inflammatory factors and matrix degradation factors and down-regulation of factors related to extracellular matrix formation by TFs in culture. ASCs did not suppress these presumably negative effects induced by IL-1β. However, ASC co-culture with M1 (pro-inflammatory) macrophages successfully suppressed the effects of M1 macrophages on TFs by inducing a phenotypic switch from a pro-inflammatory macrophage phenotype to an anti-inflammatory macrophage phenotype, thus resulting in exposure of TFs to lower levels of pro-inflammatory cytokines (e.g., IL-1β, tumor necrosis factor alpha (TNFα)).
  
  
  CONCLUSIONS
  These findings suggest that IL-1β and M1 macrophages are detrimental to tendon healing and that ASC-mediated modulation of the post-operative inflammatory response may be beneficial for tendon healing.
authors.affiliation: Department of Orthopedic Surgery, Washington University, 425 S Euclid, Box 8233, St Louis, MO, 63110, USA. cionnemanning@gmail.com.
authors.forename: Cionne N
authors.initials: CN
authors.lastname: Manning
authors.affiliation: Department of Pathology and Immunology, Washington University, 425 S Euclid, Box 8233, St Louis, MO, 63110, USA. catmartel@gmail.com.|Current address: Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada. catmartel@gmail.com.
authors.forename: Catherine
authors.initials: C
authors.lastname: Martel
authors.affiliation: Department of Biomedical Engineering, Washington University, One Brookings Drive, Campus Box 1097, St Louis, MO, USA. sakiyama@wustl.edu.
authors.forename: Shelly E
authors.initials: SE
authors.lastname: Sakiyama-Elbert
authors.affiliation: Department of Orthopedic Surgery, Washington University, 425 S Euclid, Box 8233, St Louis, MO, 63110, USA. silvam@wudosis.wustl.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Silva
authors.affiliation: Department of Orthopedic Surgery, Washington University, 425 S Euclid, Box 8233, St Louis, MO, 63110, USA. shivshah03@gmail.com.
authors.forename: Shivam
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Orthopedic Surgery, Washington University, 425 S Euclid, Box 8233, St Louis, MO, 63110, USA. gelberman@wudosis.wustl.edu.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Gelberman
authors.affiliation: Department of Orthopedic Surgery, Washington University, 425 S Euclid, Box 8233, St Louis, MO, 63110, USA. ThomopoulosS@wudosis.wustl.edu.
authors.forename: Stavros
authors.initials: S
authors.lastname: Thomopoulos
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013710:Tendons / Q000166:cytology; D014945:Wound Healing / Q000502:physiology*
chemical_list: D016207:Cytokines; C000594089:IL1B protein, rat; D053583:Interleukin-1beta