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A8.19 Locally administrated adipose derived mesenchymal stem cells reinforce their anti-inflammatory effect through IL-1β mediated attraction of neutrophils into knee joints with experimental osteoarthritis
  1. SCM van Dalen1,
  2. RFP Schelbergen1,
  3. A Slöetjes1,
  4. NAJ Cremers2,
  5. M ter Huurne1,
  6. FA Wagener2,
  7. WB van den Berg1,
  8. van Lent PLEM1
  1. 1 Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
  2. 2 Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, The Netherlands

Abstract

Introduction Osteoarthritis (OA) is characterised by cartilage breakdown and ectopic bone formation in joints. Recent studies have shown that low grade synovial inflammation, reflected by inflammatory factors like interleukin-1 beta (IL-1β), contributes to joint pathology. Recently we found that adipose derived mesenchymal stem cells (ASCs) exhibit anti-inflammatory characteristics1 and reduce joint pathology after local application into mouse knee joints with experimental OA.2 This anti-inflammatory effect is only observed after intra-articular injection in early but not late phase OA, suggesting that the effect may be mediated by pro-inflammatory mediators.1

Objective To study the effect of IL-1β on the anti-inflammatory potency of ASCs in early OA.

Methods Experimental OA was induced by injection of collagenase into murine knee joints (CIOA). Total knee joints were stained with haematoxylin/eosin and the PMN specific antibody NIMPR14. ASCs were isolated from adipose tissue and stimulated with IL-1β or interferon-gamma (IFN-γ). Gene expression in synovium and stimulated cells were analysed using qPCR. Protein levels of chemokines and cytokines were measured in the supernatant and washouts using Luminex. ASCs were co-cultured with MACS isolated bone marrow (BM-) PMNs and analysed using histology, qPCR and Luminex.

Results Injection of ASCs into day 7 CIOA knee joints (when synovitis is highest) caused a strong influx of immune cells into the joint cavity shortly after injection (6 h), which had largely disappeared after 24 h. Immunohistochemistry revealed that particularly PMN-like cells were attracted. Synovial gene expression of neutrophil attracting chemokines KC, CXCL5, and CXCL7 was increased. In line with this, IL-1β stimulated ASCs injected in naive knee joints also resulted in massive influx of PMN-like cells.

IL-1β and IFN-γ (as a positive control) stimulation of ASCs in vitro strongly enhanced gene expression of KC, CXCL5, and CXCL7 and protein levels of KC. Finally, we co-cultured ASCs with BM-PMNs in the presence of IL-1β or IFNγ. After 3 h, a clear clustering of neutrophils around ASCs was observed which significantly decreased protein levels of KC (-69% after 24 h; -76% after 48 h).

Conclusion ASCs attract PMN-like cells when injected locally into a day 7 CIOA knee-joint expressing low levels of IL-1β. In vitro, IL-1β stimulated ASCs show an increase in chemokine expression, leading to attraction and clustering with neutrophils and significantly decreased levels of pro-inflammatory factors like KC. The anti-inflammatory effect of locally applied ASCs into OA joints showing synovitis may be triggered by IL-1β and attraction of PMN-like cells.

This research was supported by the Dutch Arthritis Association.

References

  1. ter Huurne M, Schelbergen R, Blattes R, et al . Arthritis Rheum 2012; 64 :3604–13.

  2. Schelbergen RF, van Dalen S, ter Huurne M, et al . Osteoarthritis Cartilage 2014; 22 :1158–66.

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