Regenerating cartilages by engineered ASCs: Prolonged TGF-β3/BMP-6 expression improved articular cartilage formation and restored zonal structure

Chia Hsin Lu, Tsung Szu Yeh, Chia Lin Yeh, Yu Hua Dean Fang, Li Yu Sung, Shih Yeh Lin, Tzu Chen Yen, Yu Han Chang, Yu Chen Hu

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

Abstract

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-β3/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-β3/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-β3/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-β3/BMP-6 improved the chondrogenesis, in vitro cartilaginous constructs production and in vivo hyaline cartilage regeneration, thus representing a remarkable advance in cartilage engineering.

Original languageEnglish
Pages (from-to)186-195
Number of pages10
JournalMolecular Therapy
Volume22
Issue number1
DOIs
Publication statusPublished - 2014 Jan

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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