Theranostics 2018; 8(4):906-920. doi:10.7150/thno.20746

Research Paper

Mesenchymal Stromal/stem Cell-derived Extracellular Vesicles Promote Human Cartilage Regeneration In Vitro

Lucienne A. Vonk3, Sanne F. J. van Dooremalen1,2, Nalan Liv1, Judith Klumperman1, Paul J. Coffer1,2, Daniël B.F. Saris3,4,5, Magdalena J. Lorenowicz1,2✉

1. Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands;
2. Regenerative Medicine Center, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands;
3. Department of Orthopedics, University Medical Center Utrecht, Utrecht University, PO Box 85500, 3508 GA, Utrecht, The Netherlands;
4. MIRA institute, University of Twente, ME125, PO Box 217, 7500 AE, Enschede, The Netherlands;
5. Department of Orthopedics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

Abstract

Osteoarthritis (OA) is a rheumatic disease leading to chronic pain and disability with no effective treatment available. Recently, allogeneic human mesenchymal stromal/stem cells (MSC) entered clinical trials as a novel therapy for OA. Increasing evidence suggests that therapeutic efficacy of MSC depends on paracrine signalling. Here we investigated the role of extracellular vesicles (EVs) secreted by human bone marrow derived MSC (BMMSC) in human OA cartilage repair.

Methods: To test the effect of BMMSC-EVs on OA cartilage inflammation, TNF-alpha-stimulated OA chondrocyte monolayer cultures were treated with BMMSC-EVs and pro-inflammatory gene expression was measured by qRT-PCR after 48 h. To assess the impact of BMMSC-EVs on cartilage regeneration, BMMSC-EVs were added to the regeneration cultures of human OA chondrocytes, which were analyzed after 4 weeks for glycosaminoglycan content by 1,9-dimethylmethylene blue (DMMB) assay. Furthermore, paraffin sections of the regenerated tissue were stained for proteoglycans (safranin-O) and type II collagen (immunostaining).

Results: We show that BMMSC-EVs inhibit the adverse effects of inflammatory mediators on cartilage homeostasis. When co-cultured with OA chondrocytes, BMMSC-EVs abrogated the TNF-alpha-mediated upregulation of COX2 and pro-inflammatory interleukins and inhibited TNF-alpha-induced collagenase activity. BMMSC-EVs also promoted cartilage regeneration in vitro. Addition of BMMSC-EVs to cultures of chondrocytes isolated from OA patients stimulated production of proteoglycans and type II collagen by these cells.

Conclusion: Our data demonstrate that BMMSC-EVs can be important mediators of cartilage repair and hold great promise as a novel therapeutic for cartilage regeneration and osteoarthritis.

Keywords: Mesenchymal stem/stromal cells, extracellular vesicles, cartilage regeneration, inflammation, osteoarthritis.

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How to cite this article:
Vonk LA, van Dooremalen SFJ, Liv N, Klumperman J, Coffer PJ, Saris DBF, Lorenowicz MJ. Mesenchymal Stromal/stem Cell-derived Extracellular Vesicles Promote Human Cartilage Regeneration In Vitro. Theranostics 2018; 8(4):906-920. doi:10.7150/thno.20746. Available from http://www.thno.org/v08p0906.htm