title: Human osteoarthritic synovium impacts chondrogenic differentiation of mesenchymal stem cells via macrophage polarisation state.
abstract: OBJECTIVE
  Mesenchymal stem cells (MSCs) are a promising cell type for the repair of damaged cartilage in osteoarthritis (OA). However, OA synovial fluid and factors secreted by synovium impede chondrogenic differentiation of MSCs, and the mechanism responsible for this effect remains unclear. In this study, we sought to investigate whether M1 and M2 synovial macrophages can contribute to the inhibition of MSC chondrogenesis.
  
  
  METHODS
  The constitution of synovial macrophage subsets was analysed by immunohistochemical staining of human OA synovium sections for CD86 (M1 marker) and CD206 (M2 marker). To assess the effect of synovial macrophages on chondrogenesis, collagen type II (COL2) and aggrecan (ACAN) gene expression were compared between MSCs undergoing chondrogenic differentiation in medium conditioned (CM) by human OA synovial explants, human synovial macrophages and fibroblasts, or peripheral blood derived primary human monocytes differentiated towards an M1 or M2 phenotype.
  
  
  RESULTS
  OA synovium contained both M1 and M2 macrophages. Medium conditioned by synovial macrophages (CD45 + plastic adherent cells) down-regulated chondrogenic gene expression by MSCs. Additionally, CM of M1 polarised monocytes significantly decreased COL2 and ACAN gene expression by MSCs; this effect was not observed for treatment with CM of M2 polarised monocytes.
  
  
  CONCLUSIONS
  MSC chondrogenesis is inhibited by OA synovium CM through factors secreted by synovial macrophages and our findings suggest that M1 polarised subsets are potential mediators of this anti-chondrogenic effect. Modulation of macrophage phenotype may serve as a beneficial strategy to maximise the potential of MSCs for efficient cartilage repair.
authors.affiliation: Regenerative Medicine Institute, National University of Ireland Galway, Ireland; Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: n.fahy1@nuigalway.ie.
authors.forename: N
authors.initials: N
authors.lastname: Fahy
authors.affiliation: Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: m.vanmelle@erasmusmc.nl.
authors.forename: M L
authors.initials: ML
authors.lastname: de Vries-van Melle
authors.affiliation: Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: j.lehmann@erasmusmc.nl.
authors.forename: J
authors.initials: J
authors.lastname: Lehmann
authors.affiliation: Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: w.wei@erasmusmc.nl.
authors.forename: W
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; Department of Otorhinolarynogology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: n.grotenhuis@erasmusmc.nl.
authors.forename: N
authors.initials: N
authors.lastname: Grotenhuis
authors.affiliation: Regenerative Medicine Institute, National University of Ireland Galway, Ireland; Department of Oral and Maxillofacial Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: e.farrell@erasmusmc.nl.
authors.forename: E
authors.initials: E
authors.lastname: Farrell
authors.affiliation: Department of Rheumatology, Radboud University Medical Centre, Nijmegen, The Netherlands. Electronic address: p.vanderkraan@reuma.umcn.nl.
authors.forename: P M
authors.initials: PM
authors.lastname: van der Kraan
authors.affiliation: Regenerative Medicine Institute, National University of Ireland Galway, Ireland. Electronic address: mary.murphy@nuigalway.ie.
authors.forename: J M
authors.initials: JM
authors.lastname: Murphy
authors.affiliation: Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: y.bastiaansen@erasmusmc.nl.
authors.forename: Y M
authors.initials: YM
authors.lastname: Bastiaansen-Jenniskens
authors.affiliation: Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; Department of Otorhinolarynogology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: g.vanosch@erasmusmc.nl.
authors.forename: G J V M
authors.initials: GJ
authors.lastname: van Osch
mesh_terms: D000328:Adult; D000368:Aged; D053674:Aggrecans / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D002358:Cartilage, Articular / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D019742:Chemokines, CC / Q000235:genetics; D019902:Chondrocytes; D020219:Chondrogenesis / Q000276:immunology*; D024043:Collagen Type II / Q000378:metabolism; D017077:Culture Media, Conditioned; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D010003:Osteoarthritis / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000378:metabolism; D013582:Synovial Fluid / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology*
chemical_list: C508319:ACAN protein, human; D053674:Aggrecans; D051940:B7-2 Antigen; C111792:CCL18 protein, human; C497964:CD86 protein, human; D019742:Chemokines, CC; D024043:Collagen Type II; D017077:Culture Media, Conditioned; C508600:IL6 protein, human; D015850:Interleukin-6; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface
keywords: Chondrogenesis; Inflammation; Macrophage; Mesenchymal stem cells; Osteoarthritis