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AB0066 Human multipotential stromal cells express low surface levels of pro-inflammatory cytokine receptors in bone healing defects
  1. JJ El-Jawhari1,
  2. G Kleftouris1,
  3. YM El-sherbiny1,
  4. R West2,
  5. E Jones1,
  6. PV Giannoudis1
  1. 1Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM)
  2. 2Leeds Institute of Health Sciences, University of Leeds, Leeds, United Kingdom

Abstract

Background Osteoimmunology is an evolving field where the multipotential stromal cells (MSCs) can be considered as an important player linking immune response with bone generation. A group of pro-inflammatory cytokines including IFN-γ, TNF-α, IL-17 and IL-1, has been proven to have a licensing effect on MSCs promoting the immunomodulatory activities of MSCs (1). Importantly, these cytokines can regulate the osteogenic differentiation capability of MSCs and in particular, IL-1 and IL-17 can enhance the MSC osteogenesis as shown in previous in vitro studies (2,3). However, little is known about the role of these cytokine-MSC interactions in the bone-related diseases in humans.

Objectives The main focus of this study was to assess if the immune-dependent licensing process of MSCs could be involved in defective bone regeneration.

Methods We used samples of bone marrow aspirates (n=15) from two groups of traumatic bone fracture patients; normal union and non-union. Bone marrow MSCs were analyzed for the surface expression of the receptors of the pro-inflammatory licensing cytokines using flowcytometry-optimized panels. Additionally, a comparison of the cytokine effect on the proliferation of cultured MSCs was compared between normal union and non-union groups using the cell proliferation XTT test.

Results Interestingly, there were significant lower expression levels of IL-1 receptors 1 and 3 (IL-1R1 and IL-1R3) on non-union MSCs compared to normal-union MSCs (p=0.0478 and p=0.0113 respectively). Furthermore, the surface levels of TNF-αR1 (CD120a) were significantly lesser on non-union MSCs (p=0.0119). There was a clear trend of reduced expression of IL-17 receptors (CD217) on the surface of non-union MSCs, but it was not statistically significant compared to normal-union (p=0.0726). The XTT data showed a significant less proliferation index for IL-1-treated non-union MSCs compared to normal-union MSCs (p=0.0446). Also, a consistent trend of lower proliferation index of non-union MSCs was detected when these cells were treated by IFN-γ, TNF-α or IL-17.

Conclusions Together, the lower levels of the pro-inflammatory cytokine receptors indicated a possible mechanism for a defective response of non-union MSCs to the inflammatory signals (particularly IL-1). Further understating of the impact of immune-MSC interactions on human bone healing and regeneration will help to develop new therapies for musculoskeletal diseases involving osteolytic lesions.

References

  1. Mesenchymal stromal cell 'licensing': a multistep process. Krampera M. Leukemia. 2011 Sep;25(9):1408–14.

  2. Interleukin-1β induces differentiation of human mesenchymal stem cells into osteoblasts via the Wnt-5a/receptor tyrosine kinase-like orphan receptor 2 pathways. Sonomoto K, Yamaoka K, Oshita K, Fukuyo S, Zhang X, Nakano K, Okada Y, Tanaka Y. Arthritis Rheum. 2012 Oct;64(10):3355–63.

  3. Proinflammatory T cells and IL-17 stimulate osteoblast differentiation. Croes M, Öner FC, van Neerven D, Sabir E, Kruyt MC, Blokhuis TJ, Dhert WJ, Alblas J. Bone. 2016 Mar; 84:262–70.

References

Acknowledgements This project (no. S-16–132E) was supported by the AO Foundation.

Disclosure of Interest None declared

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