Engineering exosomes derived from subcutaneous fat MSCs specially promote cartilage repair as miR-199a-3p delivery vehicles in Osteoarthritis

被引:29
作者
Zhao, Shu [1 ,2 ]
Xiu, Guanghui [5 ]
Wang, Jian [1 ]
Wen, Yi [1 ]
Lu, Jinyuan [3 ]
Wu, Baitong [1 ]
Wang, Guangming [1 ]
Yang, Danjing [1 ]
Ling, Bin [5 ]
Du, Dajiang [4 ]
Xu, Jun [1 ]
机构
[1] Tongji Univ, Sch Med, Dept Gastroenterol, East Hosp, Shanghai 200120, Peoples R China
[2] Tongji Univ, Shanghai Peoples Hosp 4, Sch Med, Dept Plast Surg, Shanghai 200434, Peoples R China
[3] Tongji Univ, Tongji Hosp, Sch Med, Dept Hematol, Shanghai 200065, Peoples R China
[4] Shanghai Jiao Tong Univ, Inst Microsurg Extrem, Dept Orthoped Surg, Sch Med,Shanghai Peoples Hosp 6,Sch Med, Shanghai 200233, Peoples R China
[5] Yunnan Univ, Yunnan Univ, Peoples Hosp Yunnan Prov 2, Dept Intens Care Unit,Affiliated Hosp, Kunming 650021, Peoples R China
关键词
Engineering exosomes; Osteoarthritis; Autophagy; miR-199a-3p; Cartilage-targeted; MESENCHYMAL STEM-CELLS; AUTOPHAGY; HOMEOSTASIS; SIRNA; MTOR; CYCLOOXYGENASE-2; DESTABILIZATION; DEGENERATION; REGENERATION; MECHANISMS;
D O I
10.1186/s12951-023-02086-9
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Osteoarthritis (OA) is a degenerative joint disease involving cartilage. Exosomes derived from Mesenchymal stem cells (MSCs) therapy improves articular cartilage repair, but subcutaneous fat (SC) stromal cells derived exosomes (MSCsSC-Exos), especially engineering MSCsSC-Exos for drug delivery have been rarely reported in OA therapy. This objective of this study was to clarify the underlying mechanism of MSCsSC-Exos on cartilage repair and therapy of engineering MSCsSC-Exos for drug delivery in OA. MSCsSC-Exos could ameliorate the pathological severity degree of cartilage via miR-199a-3p, a novel molecular highly enriched in MSCsSC-Exos, which could mediate the mTOR-autophagy pathway in OA rat model. Intra-articular injection of antagomiR-199a-3p dramatically attenuated the protective effect of MSCsSC-Exos-mediated on articular cartilage in vivo. Furthermore, to achieve the superior therapeutic effects of MSCsSC-Exos on injured cartilage, engineering exosomes derived from MSCsSC as the chondrocyte-targeting miR-199a-3p delivery vehicles were investigated in vitro and in vivo. The chondrocyte-binding peptide (CAP) binding MSCsSC-Exos could particularly deliver miR-199a-3p into the chondrocytes in vitro and into deep articular tissues in vivo, then exert the excellent protective effect on injured cartilage in DMM-induced OA mice. As it is feasible to obtain human subcutaneous fat from healthy donors by liposuction operation in clinic, meanwhile engineering MSCsSC-Exos to realize targeted delivery of miR-199a-3p into chondrocytes exerted excellent therapeutic effects in OA animal model in vivo. Through combining MSCsSC-Exos therapy and miRNA therapy via an engineering approach, we develop an efficient MSCsSC-Exos-based strategy for OA therapy and promote the application of targeted-MSCsSC-Exos for drug delivery in the future.
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页数:26
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