| Objectives:Osteoarthritis(OA),the most common chronic degenerative joint disease,is characterized by progressive destruction of articular cartilage.Current pharmacological administration,including nonsteroidal anti-inflammatory drugs(NSAIDs),analgesics and intraarticular injection of hyaluronic acid,mainly focus on temporarily alleviating OA symptoms rather than reversing OA process.Surgical interventions are also developed for management of cartilage defects.Microfracture(MF)technique can stimulate bone marrow mesenchymal stem cells(MSCs)to repair cartilage defects.However,MF often results in the formation of fibrocartilage but not hyaline cartilage so that cartilage degeneration only delays in the short term.Autologous chondrocyte implantation(ACI)shows superior outcomes compared to MF in cartilage repair,while the complex procedure and unclear long-term impact on donor area limit its application.Thus,development of new approaches that can promote cartilage regeneration is highly desired.In recent years,stem cell therapy has drawn considerable attention in OA treatment.MSCs are multipotent progenitor cells that can be isolated from various tissues,such as bone marrow,adipose tissue and peripheral blood.These cells exhibit self-renewal and multi-lineage differentiation properties(i.e.adipocytes,osteoblasts and chondrocytes).However,as to cartilage regeneration,several randomized controlled trials show that the effect of MSCs therapy on cartilage repair is not evident.Given the fact that MSCs exhibit low chondrogenic differentiation efficiency in OA-related microenvironment with low chondrogenesis indicators(e.g.transforming growth factor-β(TGF-β),MSCs tend to differentiate into fibroelastosis-like tissue instead of hyaline cartilage.Methods:Toward this goal,we synthesized cupper sulfide(CuS)nanoparticles(NPs)because our previous research showed that Cu could enhance chondrogenesis of MSCs.Then CuS NPs were modified with 3-aminopropyltriethoxysilane(APTES)to obtained CuS-NH2,facilitating the electrostatic binding with the negatively charged plasmid DNA encoding TGF-β1.Since nanoengineering of MSCs requires NPs with good biosafety and high cellular uptake rate,we further coated CuS/TGF-β1 NPs with phosphatidylcholine(PC).PC is one of the basic components of mammalian cell membrane,and thus biomimetic CuS/TGF-β1@PC(CTP)could effectively transfer pDNA into MSCs with low cytotoxicity.Results:The CuS/TGF-β1@PC NP-engineered MSCs(termed CTP-MSCs)exhibited enhanced cell migration,chondrogenesis,and inhibition on extracellular matrix(ECM)degradation compared to pure MSCs.We found that the NPs not only promoted cell proliferation and migration,but also presented a higher pDNA transfection efficiency relative to commercial transfection reagent lipofectamine 3000.The resultant CuS-TGF-β1@PC NP-engineered MSCs(termed CTP-MSCs)were better than pure MSCs in terms of chondrogenic gene expression,glycosaminoglycan deposition and type Ⅱ collagen formation,favoring cartilage repair.Further,CTP-MSCs inhibited extracellular matrix degradation in interleukin-1β-induced chondrocytes.Consequently,intraarticular administration of CTP-MSCs significantly enhanced the repair of damaged cartilage,whereas pure MSCs exhibited very limited effects on cartilage regeneration in destabilization of the medial meniscus(DMM)surgical instability mice.Conclusions:In summary,we developed CuS/TGF-β1@PC NP-engineered MSCs as a new modality for OA treatment.The resultant CTP-MSCs bore three highly desired functions for stem cell-based therapy in OA,including accelerated cell proliferation and migration,enhanced chondrogenesis,and inhibition of extracellular matrix degradation.Moreover,CTP-MSCs did not cause any adverse effects on main organs as well as liver and kidney functions.Hence,the nanoengineered MSCs could provide an efficient and safe strategy to overcome limitations of current stem cell therapy and achieve a successful OA treatment. |
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