Journal
MOLECULAR THERAPY
Volume 22, Issue 1, Pages 186-195Publisher
CELL PRESS
DOI: 10.1038/mt.2013.165
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Funding
- National Tsing Hua University (Toward World-Class University Project) [102N2051E1]
- National Tsing Hua University (NTHU-CGMH Joint Research Program) [100N7753E1, 101N2753E1, 102N2766E1]
- CGMH Intramural Project [CMRPG3C0161, CMRPG3B0431, CMRPG3B0411, CMRPG300131]
- National Science Council, Taiwan [101-2628-E-007-009-MY3, 101-2923-E-007-002-MY3]
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Adipose-derived stem cells (ASCs) hold promise for cartilage regeneration but their chondrogenesis potential is inferior. Here, we used a baculovirus (BV) system that exploited FLPo/Frt-mediated transgene recombination and episomal minicircle formation to genetically engineer rabbit ASCs (rASCs). The BV system conferred prolonged and robust TGF-beta 3/BMP-6 expression in rASCs cultured in porous scaffolds, which critically augmented rASCs chondrogenesis and suppressed osteogenesis/hypertrophy, leading to the formation of cartilaginous constructs with improved maturity and mechanical properties in 2-week culture. Twelve weeks after implantation into full-thickness articular cartilage defects in rabbits, these engineered constructs regenerated neocartilages that resembled native hyaline cartilages in cell morphology, matrix composition and mechanical properties. The neocartilages also displayed cartilage-specific zonal structures without signs of hypertrophy and degeneration, and eventually integrated with host cartilages. In contrast, rASCs that transiently expressed TGF-beta 3/BMP-6 underwent osteogenesis/hypertrophy and resulted in the formation of inferior cartilaginous constructs, which after implantation regenerated fibrocartilages. These data underscored the crucial role of TGF-beta 3/BMP-6 expression level and duration in rASCs in the cell differentiation, constructs properties and in vivo repair. The BV-engineered rASCs that persistently express TGF-beta 3/BMP-6 improved the chondrogenesis, in vitro cartilaginous constructs production and in vivo hyaline cartilage regeneration, thus representing a remarkable advance in cartilage engineering.
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