MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity

被引:687
作者
Zhang, Shipin [1 ]
Chuah, Shang Jiunn [1 ]
Lai, Ruenn Chai [2 ]
Hui, James Hoi Po [3 ,4 ]
Lim, Sai Kiang [2 ,5 ]
Toh, Wei Seong [1 ,4 ]
机构
[1] Natl Univ Singapore, Fac Dent, 11 Lower Kent Ridge Rd, Singapore 119083, Singapore
[2] Agcy Sci Technol & Res, Inst Med Biol, Singapore, Singapore
[3] Natl Univ Singapore, Natl Univ Hlth Syst, Dept Orthopaed Surg, Cartilage Repair Program,Therapeut Tissue Engn La, Singapore, Singapore
[4] Natl Univ Singapore, Life Sci Inst, Tissue Engn Program, Singapore, Singapore
[5] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore, Singapore
基金
英国医学研究理事会;
关键词
Mesenchymal stem cells; Exosomes; Cartilage; Regeneration; Chondrocytes; Macrophages; MESENCHYMAL STEM-CELLS; HUMAN ARTICULAR CHONDROCYTES; GENE-EXPRESSION; IN-VITRO; METALLOPROTEINASES-3; GENE; TISSUE INHIBITOR; TGF-BETA; OSTEOARTHRITIS; CHONDROGENESIS; INFLAMMATION;
D O I
10.1016/j.biomaterials.2017.11.028
中图分类号
R318 [生物医学工程];
学科分类号
0831 ;
摘要
Mesenchymal stem cell (MSC) exosome was previously shown to be effective in repairing critical size osteochondral defects in an immunocompetent rat model. Here we investigate the cellular processes modulated by MSC exosomes and the mechanism of action underlying the exosome-mediated responses in cartilage repair. We observed that exosome-mediated repair of osteochondral defects was characterised by increased cellular proliferation and infiltration, enhanced matrix synthesis and a regenerative immune phenotype. Using chondrocyte cultures, we could attribute the rapid cellular proliferation and infiltration during exosome-mediated cartilage repair to exosomal CD73-mediated adenosine activation of AKT and ERK signalling. Inhibitors of AKT or ERK phosphorylation suppressed exosome-mediated increase in cell proliferation and migration but not matrix synthesis. The role of exosomal CD73 was confirmed by the attenuation of ART and ERK signalling by AMPCP, a CD73 inhibitor and theophylline, an adenosine receptor antagonist. Exosome-treated defects also displayed a regenerative immune phenotype characterised by a higher infiltration of CD163(+) regenerative M2 macrophages over CD86(+) M1 macrophages, with a concomitant reduction in pro-inflammatory synovial cytokines IL-1 beta and TNF-alpha. Together, these observations demonstrated that the efficient osteochondral regeneration by MSC exosomes was effected through a coordinated mobilisation of multiple cell types and activation of several cellular processes. (C) 2017 Elsevier Ltd. All rights reserved.
引用
收藏
页码:16 / 27
页数:12
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