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

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• 作者：Chin-Yu Lin^a ; ¹ ; Yu-Han Chang^b ; ^c ; ¹ ; Chun-Yu Kao^a ; Chia-Hsin Lu^a ; Li-Yu Sung^a ; Tzu-Chen Yen^b ; ^d ; Kun-Ju Lin^d ; ^e ; ^{lin4857@adm.cgmh.org.tw} ; Yu-Chen Hu^a ; ^f ; ^{ychu@mx.nthu.edu.tw} ; ^{yuchen@che.nthu.edu.tw}
• 关键词：Baculovirus ; Mesenchymal stem cells ; Gene therapy ; Calvarial bone defect ; Tissue engineering ; Sustained expression
• 刊名：Biomaterials
• 出版年：2012
• 期刊代码：7_01429612
• 类别：ms
• 出版时间：May, 2012
• 卷：33
• 期：14
• 页码：3682-3692
• 文件大小：2417 K

摘要

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, 渭CT and histological analyses demonstrated that the sustained BMP2/VEGF expression remarkably ameliorated the angiogenesis and regeneration of critical-size (8聽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 鈮?3%of the area and 鈮?3%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.