Exosomes from adipose‑derived stem cells promote chondrogenesis and suppress inflammation by upregulating miR‑145 and miR‑221

Zhao,Chen; Chen,Jin‑Yang; Peng,Wen‑Ming; Yuan,Bo; Bi,Qing; Xu,You‑Jia

doi:10.3892/mmr.2020.10982

Exosomes from adipose‑derived stem cells promote chondrogenesis and suppress inflammation by upregulating miR‑145 and miR‑221

Authors:
- Chen Zhao
- Jin‑Yang Chen
- Wen‑Ming Peng
- Bo Yuan
- Qing Bi
- You‑Jia Xu
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Affiliations: Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China, Research and Development Department, Zhejiang Healthfuture Institute for Cell‑Based Applied Technology, Hangzhou, Zhejiang 310052, P.R. China, Department of Orthopedics, Tonglu TCM Hospital, Hangzhou, Zhejiang 311500, P.R. China, Department of Orthopedics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
Published online on: February 7, 2020 https://doi.org/10.3892/mmr.2020.10982
Pages: 1881-1889
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Osteoarthritis (OA) is one of the most prevalent joint disorders globally. Patients suffering from OA are often obese and adiposity is linked to chronic inflammation. In the present study, the potential of using exosomes isolated from adipose‑derived stem cells (ADSCs) as a therapeutic tool for reducing chronic inflammation and promoting chondrogenesis was investigated using patient‑derived primary cells. First, it was tested whether patient‑derived ADSCs could differentiate into chondrogenic and osteogenic lineages. The ADSCs were then used as a source of exosomes. It was found that exosomes isolated from ADSCs, when co‑cultured with activated synovial fibroblasts, downregulated the expression of pro‑inflammatory markers interleukin (IL)‑6, NF‑κB and tumor necrosis factor‑α, while they upregulated the expression of the anti‑inflammatory cytokine IL‑10; without exosomes, the opposite observations were made. In addition, inflammation‑inflicted oxidative stress was induced in vitro by stimulating chondrocytes with H2O2. Treatment with exosomes protected articular chondrocytes from H2O2‑induced apoptosis. Furthermore, exosome treatment promoted chondrogenesis in periosteal cells and increased chondrogenic markers, including Collagen type II and β‑catenin; inhibition of Wnt/β‑catenin, using the antagonist ICG‑001, prevented exosome‑induced chondrogenesis. Periosteal cells treated with exosomes exhibited higher levels of microRNA (miR)‑145 and miR‑221. The upregulation of miR‑145 and miR‑221 was associated with the enhanced proliferation of periosteal cells and chondrogenic potential, respectively. The present study provided evidence in support for the use of patient‑derived exosomes, produced from ADSCs, for potential chondrogenic regeneration and subsequent amelioration of osteoarthritis.

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1	Xia B, Di Chen, Zhang J, Hu S, Jin H and Tong P: Osteoarthritis pathogenesis: A review of molecular mechanisms. Calcif Tissue Int. 95:495–505. 2014. View Article : Google Scholar : PubMed/NCBI
2	Felson DT, Lawrence RC, Dieppe PA, Hirsch R, Helmick CG, Jordan JM, Kington RS, Lane NE, Nevitt MC, Zhang Y, et al: Osteoarthritis: New insights. Part 1: The disease and its risk factors. Ann Intern Med. 133:635–646. 2000. View Article : Google Scholar : PubMed/NCBI
3	Ashford S and Williard J: Osteoarthritis: A review. Nurse Pract. 39:1–8. 2014. View Article : Google Scholar : PubMed/NCBI
4	Gokce A, Peak TC, Abdel-Mageed AB and Hellstrom WJ: Adipose Tissue-derived stem cells for the treatment of erectile dysfunction. Curr Urol Rep. 17:142016. View Article : Google Scholar : PubMed/NCBI
5	Sabol RA, Bowles AC, Cote A, Wise R, Pashos N and Bunnell BA: Therapeutic potential of adipose stem cells. Adv Exp Med Biol. Jul 27–2018.doi: 10.1007/5584_2018_248 (Epub ahead of print). View Article : Google Scholar : PubMed/NCBI
6	Pak J, Lee JH, Pak N, Pak Y, Park KS, Jeon JH, Jeong BC and Lee SH: Cartilage regeneration in humans with adipose tissue-derived stem cells and adipose stromal vascular fraction cells: Updated status. Int J Mol Sci. 19(pii): E21462018. View Article : Google Scholar : PubMed/NCBI
7	Simpson RJ, Lim JW, Moritz RL and Mathivanan S: Exosomes: Proteomic insights and diagnostic potential. Expert Rev Proteomics. 6:267–283. 2009. View Article : Google Scholar : PubMed/NCBI
8	Tran TH, Mattheolabakis G, Aldawsari H and Amiji M: Exosomes as nanocarriers for immunotherapy of cancer and inflammatory diseases. Clin Immunol. 160:46–58. 2015. View Article : Google Scholar : PubMed/NCBI
9	Barile L and Vassalli G: Exosomes: Therapy delivery tools and biomarkers of diseases. Pharmacol Ther. 174:63–78. 2017. View Article : Google Scholar : PubMed/NCBI
10	Li Z, Wang Y, Xiao K, Xiang S, Li Z and Weng X: Emerging role of exosomes in the joint diseases. Cell Physiol Biochem. 47:2008–2017. 2018. View Article : Google Scholar : PubMed/NCBI
11	Arai Y, Park S, Choi B, Ko KW, Choi WC, Lee JM, Han DW, Park HK, Han I, Lee JH and Lee SH: Enhancement of Matrix Metalloproteinase-2 (MMP-2) as a potential chondrogenic marker during chondrogenic differentiation of human adipose-derived stem cells. Int J Mol Sci. 17(pii): E9632016. View Article : Google Scholar : PubMed/NCBI
12	Zimmermann T, Kunisch E, Pfeiffer R, Hirth A, Stahl HD, Sack U, Laube A, Liesaus E, Roth A, Palombo-Kinne E, et al: Isolation and characterization of rheumatoid arthritis synovial fibroblasts from primary culture-primary culture cells markedly differ from fourth-passage cells. Arthritis Res. 3:72–76. 2001. View Article : Google Scholar : PubMed/NCBI
13	Dai M, Sui B, Xue Y, Liu X and Sun J: Cartilage repair in degenerative osteoarthritis mediated by squid type II collagen via immunomodulating activation of M2 macrophages, inhibiting apoptosis and hypertrophy of chondrocytes. Biomaterials. 180:91–103. 2018. View Article : Google Scholar : PubMed/NCBI
14	Goldring MB: The role of cytokines as inflammatory mediators in osteoarthritis: Lessons from animal models. Connect Tissue Res. 40:1–11. 1999. View Article : Google Scholar : PubMed/NCBI
15	Naito M, Ohashi A and Takahashi T: Dexamethasone inhibits chondrocyte differentiation by suppression of Wnt/β-catenin signaling in the chondrogenic cell line ATDC5. Histochem Cell Biol. 144:261–272. 2015. View Article : Google Scholar : PubMed/NCBI
16	Yuan X, Liu H, Huang H, Liu H, Li L, Yang J, Shi W, Liu W and Wu L: The key role of canonical Wnt/β-catenin signaling in cartilage chondrocytes. Curr Drug Targets. 17:475–484. 2016. View Article : Google Scholar : PubMed/NCBI
17	Goldring MB: Anticytokine therapy for osteoarthritis. Expert Opin Biol Ther. 1:817–829. 2001. View Article : Google Scholar : PubMed/NCBI
18	Sutton S, Clutterbuck A, Harris P, Gent T, Freeman S, Foster N, Barrett-Jolley R and Mobasheri A: The contribution of the synovium, synovial derived inflammatory cytokines and neuropeptides to the pathogenesis of osteoarthritis. Vet J. 179:10–24. 2009. View Article : Google Scholar : PubMed/NCBI
19	Miana VV and Gonzalez EAP: Adipose tissue stem cells in regenerative medicine. Ecancermedicalscience. 12:8222018. View Article : Google Scholar : PubMed/NCBI
20	Eirin A, Riester SM, Zhu XY, Tang H, Evans JM, O'Brien D, van Wijnen AJ and Lerman LO: MicroRNA and mRNA cargo of extracellular vesicles from porcine adipose tissue-derived mesenchymal stem cells. Gene. 551:55–64. 2014. View Article : Google Scholar : PubMed/NCBI
21	Baglio SR, Rooijers K, Koppers-Lalic D, Verweij FJ, Perez Lanzon M, Zini N, Naaijkens B, Perut F, Niessen HW, Baldini N and Pegtel DM: Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res Ther. 6:1272015. View Article : Google Scholar : PubMed/NCBI
22	Hu G, Zhao X, Wang C, Geng Y, Zhao J, Xu J, Zuo B, Zhao C, Wang C and Zhang X: MicroRNA-145 attenuates TNF-α-driven cartilage matrix degradation in osteoarthritis via direct suppression of MKK4. Cell Death Dis. 8:e31402017. View Article : Google Scholar : PubMed/NCBI
23	Zheng X, Zhao FC, Pang Y, Li DY, Yao SC, Sun SS and Guo KJ: Downregulation of miR-221-3p contributes to IL-1β-induced cartilage degradation by directly targeting the SDF1/CXCR4 signaling pathway. J Mol Med (Berl). 95:615–627. 2017. View Article : Google Scholar : PubMed/NCBI
24	Zhang Y, Gao Y, Cai L, Li F, Lou Y, Xu N, Kang Y and Yang H: MicroRNA-221 is involved in the regulation of osteoporosis through regulates RUNX2 protein expression and osteoblast differentiation. Am J Transl Res. 9:126–135. 2017.PubMed/NCBI