N Fahy1, M L de Vries-van Melle2, J Lehmann3, W Wei4, N Grotenhuis5, E Farrell6, P M van der Kraan7, J M Murphy8, Y M Bastiaansen-Jenniskens9, G J V M van Osch10. 1. 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. 2. Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: m.vanmelle@erasmusmc.nl. 3. Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: j.lehmann@erasmusmc.nl. 4. Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: w.wei@erasmusmc.nl. 5. 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. 6. 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. 7. Department of Rheumatology, Radboud University Medical Centre, Nijmegen, The Netherlands. Electronic address: p.vanderkraan@reuma.umcn.nl. 8. Regenerative Medicine Institute, National University of Ireland Galway, Ireland. Electronic address: mary.murphy@nuigalway.ie. 9. Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: y.bastiaansen@erasmusmc.nl. 10. 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.
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. DESIGN: 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. CONCLUSION: 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.
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. DESIGN: 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. CONCLUSION: 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.
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