Augmented healing of critical-size calvarial defects by baculovirus-engineered MSCs that persistently express growth factors

作者：Lin Chin Yu; Chang Yu Han; Kao Chun Yu; Lu Chia Hsin; Sung Li Yu; Yen Tzu Chen; Lin Kun Ju; Hu Yu Chen^*

来源：Biomaterials, 2012, 33(14): 3682-3692.

DOI：10.1016/j.biomaterials.2012.02.007

• Baculovirus
• Mesenchymal stem cells
• Gene therapy
• Calvarial bone defect
• Tissue engineering
• Sustained expression

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.

• 出版日期2012-5
• 单位长春大学; 清华大学