期刊
BIOMATERIALS
卷 33, 期 14, 页码 3682-3692出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2012.02.007
关键词
Baculovirus; Mesenchymal stem cells; Gene therapy; Calvarial bone defect; Tissue engineering; Sustained expression
资金
- VTY Joint Research Program
- Tsou's Foundation [VGHUST99-P5-21]
- National Tsing Hua University (Toward World-Class University) [100N2050E1, 99N2544E1]
- CGMH-NTHU [99N2419E1, CMRPG390141, CMRPG300161, CMRPG300131, CMRPG380101]
- CGMH [CMRPG391721, CMRPG381001]
Repair of large calvarial bony defects remains clinically challenging because successful spontaneous calvarial re-ossification rarely occurs. Although bone marrow-derived mesenchymal stem cells (BMSCs) genetically engineered with baculovirus (BV) for transient expression of osteogenic/angiogenic factors hold promise for bone engineering, we hypothesized that calvarial bone healing necessitates prolonged growth factor expression. Therefore, we employed a hybrid BV vector system whereby one BV expressed FLP while the other harbored the BMP2 (or VEGF) cassette flanked by Frt sequences. Transduction of rabbit BMSCs with the FLP/Frt-based BV vector led to FLP-mediated episome formation, which not only extended the BMP2/VEGF expression beyond 28 days but augmented the BMSCs osteogenesis. After allotransplantation into rabbits, X-ray, PET/CT, mu CT and histological analyses demonstrated that the sustained BMP2/VEGF expression remarkably ameliorated the angiogenesis and regeneration of critical-size (8 mm) calvarial defects, when compared with the group implanted with BMSCs transiently expressing BMP2/VEGF. The prolonged expression by BMSCs accelerated the bone remodeling and regenerated the bone through the natural intramembranous pathway, filling approximate to 83% of the area and approximate to 63% of the volume in 12 weeks. These data implicated the potential of the hybrid BV vector to engineer BMSCs for sustained BMP2/VEGF expression and the repair of critical-size calvarial defects. (C) 2012 Elsevier Ltd. All rights reserved.
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