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Cell Journal، جلد ۱۵، شماره Suppl ۱، صفحات ۱۱-۱۱
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عنوان انگلیسی Is-22: Engineering Chondrogenesis with Growth Factor and Antisense Co-Transgenic Synovial Mesenchymal Stem Cells (SMSCs)
چکیده انگلیسی مقاله Articular diseases such as osteoarthritis are always a cause of suffering and pain among the elderly. Reparation and regeneration of articular cartilage tissues defected by ageing, disease or trauma have been an unmet need. The therapeutic efficacy of traditional treatments remains suboptimal. Hereby we propose to combine the recent developments in gene therapy and tissue engineering to provide a promising solution for this unmet challenge. Synovial mesenchymal stem cells (SMSCs) have been recently found to be an excellent source for cell-based chondrogenesis due to its abundance, self-renewal ability and superiority in chondrogenesis. To successfully drive SMSCs to differentiate into chondrocytes, a member of the transforming growth factor superfamily, namely transforming growth factor β3 (TGF-β3), has been studied and found to be effective in the induction of chondrogenesis. In our previous study, SMSCs have also been successfully induced to differentiate into chondrocytes with released TGF-β3 mediated by recombinant adenovirus. However, one obstacle in chondrogenesis with SMSCs is that type 1 collagen is expressed in SMSCs inherently, which will compromise cartilage functions and therefore is strictly undesired in cartilage formation. It was also found that type 1 collagen expression will be elevated by the addition or release of TGF-β3. Accordingly, RNA interference (RNAi) technology has provided a good solution for this problem. Viral vectors are efficient vehicles in terms of transduction efficiency and long-term expression, whereas the non-viral delivery of these substances is not efficient enough and only induces transient functions that may not last in the long term. In our study, we have successfully constructed a series of recombinant adenoviruses to express TGF-β3 and/or small hairpin RNA (shRNA) against type 1 collagen. Although our recombinant adenovirus can function to inhibit type 1 collagen expression, it is worthy of investigation whether a more sustained expression/ release of shRNA and/or TGF-β3 would perform better. It is therefore of great significance to study the effect of the sustained release/expression of TGF-β3 and shRNA mediated by integrative lentiviral vectors. Currently, we have established a system to engineer a type 1 collagen-suppressed cartilage construct with SMSCs. A series of recombinant adeno- and lentiviral vectors that encode TGF-β3 and/or a shRNA based antisense targeting type 1 collagen were constructed. To fulfil the expected two functions simultaneously- that is, to express TGF-β3 and suppress type 1 collagen expression, we constructed a viral vector that merges the two functions into one vector, while also co-transduced with two single-functioning vectors that express TGF-β3 and type 1 collagen-targeted shRNA, respectively. To generate tissues for articular cartilage restoration, SMSCs transduced with various combinations of these viral vectors express promotional TGFβ3 to facilitate chondrogenic differentiation and growth of SMSCs, and simultaneously down-regulate the expression of type 1 collagen for better property and maintenance of the neo-tissue desired as articular hyaline cartilage. The various combinations of either recombinant adenovirus or lentivirus implement a controlled release/ expression of either TGF-β3 or anti-type 1 collagen shRNA in a transient or permanent manner. These viral vector transducing systems were applied coupling with a hydrogel scaffold based 3D culture system. By comparison between the various groups in terms of chondrogenic induction and type 1 collagen suppression, the optimal scheme is selected and established as a sound system for the engineering of a successful cartilage construct.
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نشانی اینترنتی http://celljournal.org/journal/article/abstract/787
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