Exosomes Derived from MiR-92a-3p-overexpressing Human Mesenchymal Stem Cells Enhance Chondrogenesis and Suppress Cartilage Degradation Via Targeting WNT5A

Overview

Journal Stem Cell Res Ther

Publisher Biomed Central

Date 2018 Sep 28

PMID 30257711

Citations 220

Authors

Guping Mao

Ziji Zhang

Shu Hu

Zhiqi Zhang

Zongkun Chang

Zhiyu Huang

Weiming Liao

Yan Kang

Affiliations

Soon will be listed here.

Abstract

Background: WNT5A is known to be involved in the pathogenesis of osteoarthritis. This study investigated the molecular mechanism of exosomal miR-92a-3p and WNT5A in chondrogenesis and cartilage degeneration.

Methods: Exosomal miR-92a-3p expression was assessed in vitro in a human mesenchymal stem cell (MSC) model of chondrogenesis and in normal and OA primary human chondrocytes (PHCs). MSCs and PHCs were treated with exosomes derived from MSC-miR-92a-3p (MSC-miR-92a-3p-Exos) or its antisense inhibitor (MSC-anti-miR-92a-3p-Exos), respectively. Small interfering RNAs (siRNAs) and luciferase reporter assay were used to reveal the molecular role of exosomal miR-92a-3p and WNT5A in chondrogenesis. The protective effect of exosomes in vivo was measured using Safranin-O and Fast Green staining and immunohistochemical staining.

Results: Exosomal miR-92a-3p expression was elevated in the MSC chondrogenic exosome, while it was significantly reduced in the OA chondrocyte-secreted exosome compared with normal cartilage. Treatment with MSC-miR-92a-3p-Exos promoted cartilage proliferation and matrix genes expression in MSCs and PHCs, respectively. In contrast, treatment with MSC-anti-miR-92a-3p-Exos repressed chondrogenic differentiation and reduced cartilage matrix synthesis by enhancing the expression of WNT5A. Luciferase reporter assay demonstrated that miR-92a-3p suppressed the activity of a reporter construct containing the 3'-UTR and inhibited WNT5A expression in both MSCs and PHCs. MSC-miR-92a-3p-Exos inhibit cartilage degradation in the OA mice model.

Conclusions: Our results suggest that exosomal miR-92a-3p regulates cartilage development and homeostasis by directly targeting WNT5A. This indicates that exosomal miR-92a-3p may act as a Wnt inhibitor and exhibits potential as a disease-modifying osteoarthritis drug.

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References

Kobayashi M, Squires G, Mousa A, Tanzer M, Zukor D, Antoniou J . Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage. Arthritis Rheum. 2005; 52(1):128-35. DOI: 10.1002/art.20776. View

Yu S, Hunter D . Intra-articular therapies for osteoarthritis. Expert Opin Pharmacother. 2016; 17(15):2057-71. DOI: 10.1080/14656566.2016.1232396. View

Chun J, Oh H, Yang S, Park M . Wnt signaling in cartilage development and degeneration. BMB Rep. 2008; 41(7):485-94. DOI: 10.5483/bmbrep.2008.41.7.485. View

Lai R, Arslan F, Lee M, Sze N, Choo A, Chen T . Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010; 4(3):214-22. DOI: 10.1016/j.scr.2009.12.003. View

Mao G, Wu P, Zhang Z, Zhang Z, Liao W, Li Y . MicroRNA-92a-3p Regulates Aggrecanase-1 and Aggrecanase-2 Expression in Chondrogenesis and IL-1β-Induced Catabolism in Human Articular Chondrocytes. Cell Physiol Biochem. 2017; 44(1):38-52. DOI: 10.1159/000484579. View

Greening D, Xu R, Ji H, Tauro B, Simpson R . A protocol for exosome isolation and characterization: evaluation of ultracentrifugation, density-gradient separation, and immunoaffinity capture methods. Methods Mol Biol. 2015; 1295:179-209. DOI: 10.1007/978-1-4939-2550-6_15. View

Staines K, MacRae V, Farquharson C . Cartilage development and degeneration: a Wnt Wnt situation. Cell Biochem Funct. 2012; 30(8):633-42. DOI: 10.1002/cbf.2852. View

Hosseini-Farahabadi S, Geetha-Loganathan P, Fu K, Nimmagadda S, Yang H, Richman J . Dual functions for WNT5A during cartilage development and in disease. Matrix Biol. 2013; 32(5):252-64. DOI: 10.1016/j.matbio.2013.02.005. View

Vonk L, van Dooremalen S, Liv N, Klumperman J, Coffer P, Saris D . Mesenchymal Stromal/stem Cell-derived Extracellular Vesicles Promote Human Cartilage Regeneration . Theranostics. 2018; 8(4):906-920. PMC: 5817101. DOI: 10.7150/thno.20746. View

10.

Ning G, Liu X, Dai M, Meng A, Wang Q . MicroRNA-92a upholds Bmp signaling by targeting noggin3 during pharyngeal cartilage formation. Dev Cell. 2013; 24(3):283-95. DOI: 10.1016/j.devcel.2012.12.016. View

11.

Daheshia M, Yao J . The interleukin 1beta pathway in the pathogenesis of osteoarthritis. J Rheumatol. 2008; 35(12):2306-12. DOI: 10.3899/jrheum.080346. View

12.

Meng F, Chen W, Huang G, He A, Hou C, Long Y . MicroRNA-320 regulates matrix metalloproteinase-13 expression in chondrogenesis and interleukin-1β-induced chondrocyte responses. Osteoarthritis Cartilage. 2016; 24(5):932-41. DOI: 10.1016/j.joca.2015.12.012. View

13.

Loeser R, Goldring S, Scanzello C, Goldring M . Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012; 64(6):1697-707. PMC: 3366018. DOI: 10.1002/art.34453. View

14.

Huang G, Chubinskaya S, Liao W, Loeser R . Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes. Osteoarthritis Cartilage. 2017; 25(9):1505-1515. PMC: 5565712. DOI: 10.1016/j.joca.2017.05.018. View

15.

Toh W, Foldager C, Pei M, Hui J . Advances in mesenchymal stem cell-based strategies for cartilage repair and regeneration. Stem Cell Rev Rep. 2014; 10(5):686-96. DOI: 10.1007/s12015-014-9526-z. View

16.

Tao S, Yuan T, Zhang Y, Yin W, Guo S, Zhang C . Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics. 2017; 7(1):180-195. PMC: 5196895. DOI: 10.7150/thno.17133. View

17.

Zhang S, Chuah S, Lai R, Hui J, Lim S, Toh W . MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials. 2017; 156:16-27. DOI: 10.1016/j.biomaterials.2017.11.028. View

18.

Kawakami Y, Wada N, Nishimatsu S, Ishikawa T, Noji S, Nohno T . Involvement of Wnt-5a in chondrogenic pattern formation in the chick limb bud. Dev Growth Differ. 1999; 41(1):29-40. DOI: 10.1046/j.1440-169x.1999.00402.x. View

19.

Chen T, Lim S . Measurement of precursor miRNA in exosomes from human ESC-derived mesenchymal stem cells. Methods Mol Biol. 2013; 1024:69-86. DOI: 10.1007/978-1-62703-453-1_6. View

20.

da Silva Meirelles L, Maria Fontes A, Covas D, Caplan A . Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 2009; 20(5-6):419-27. DOI: 10.1016/j.cytogfr.2009.10.002. View