期刊
BIOMATERIALS
卷 50, 期 -, 页码 98-106出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2015.01.052
关键词
Adipose-derived stem cells; Baculovirus; Minipig; Pre-clinical; Massive bone defects; Gene therapy
资金
- National Tsing Hua University (Toward World-Class University Project) [103N2051N1]
- National Tsing Hua University (NTHU-CGMH Joint Research Program) [102N2766E1, 103N2758E1]
- CGMH Intramural Project [CMRPG3B0431, CMRPG3E0061, CMRPG3C0181, CMRPG3B1541, CMRPG3B1542, CMRPG3D0591]
- Ministry of Science and Technology, Taiwan [NSC 101-2628-E-007-009-MY3, NSC 101-2923-E-007-002-MY3, MOST 103-2622-E-007-025]
Adipose-derived stem cells (ASCs) hold promise for bone regeneration but possess inferior osteogenesis potential. Allotransplantation of ASCs engineered with the BMP2/VEGF-expressing baculoviruses into rabbits healed critical-size segmental bone defects. To translate the technology to clinical applications, we aimed to demonstrate massive bone healing in minipigs that more closely mimicked the clinical scenarios, using a new hybrid baculovirus system consisting of BacFLPo expressing the codon-optimized FLP recombinase (FLPo) and the substrate baculovirus harboring the transgene flanked by Frt sequences. Co-transduction of minipig ASCs (pASCs) with BacFLPo and the substrate baculovirus enabled transgene cassette excision, recombination and minicircle formation in approximate to 73.7% of pASCs, which substantially prolonged the transgene (BMP2 and VEGF) expression to 28 days. When encoding BMP2, the FLPo/Frt-based system augmented the pASCs osteogenesis. Allotransplantation of the BMP2/VEGF-expressing pASCs into minipigs healed massive segmental bone defects (30 mm in length) at the mid-diaphysis of femora, as evaluated by computed tomography, positron emission tomography, histology, immunohistochemical staining and biochemical testing. The defect size was approximate to 15% of femoral length in minipigs and was equivalent to approximate to 60-70 mm of femoral defect in humans, thus the healing using pASCs engineered with the FLPo/Frt-based baculovirus represented a remarkable advance for the treatment of massive bone defects. (C) 2015 Elsevier Ltd. All rights reserved.
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