Abstract
Bony defects in the craniofacial skeleton remain a challenging health concern. Our previous studies have shown that baculovirus (BV)-mediated gene therapy combined with adipose-derived mesenchymal stem cell (ASCs) to persistently express BMP-2 can improve the femoral bone defects. However, complete repair of the calvarial bone defects using the BV-mediated ASCs therapy remained difficult. Stromal cell-derived factor 1 (SDF-1) is a chemokine that can recruit mesenchymal stem cell (MSCs). Because of the inferior osteogenesis of ASCs, we hypothesized that implantation of ASCs persistently co-expressing SDF-1 and BMP-2 can recruit host MSCs and promote the osteogenic ability of ASCs, which synergistically promote calvarial bone healing. Therefore, we constructed a new Cre/loxP-based BV system encoding SDF-1 and BMP-2. Transduction of the rat ASCs with the new BV system conferred prolonged SDF-1 and BMP-2 co-expression, which recruited MSC in the transwell migration and synergistically promoted the osteogenic differentiation of transduced ASCs through Smad pathway and MAPK/ERK pathway in vitro. Furthermore, implantation of the ASCs co-expressing BMP-2/SDF-1 into critical-size (6 mm in diameter) calvarial bone defects in SD rat accelerated the bone healing, filling »70% of bone volume with native calvaria-like flat bone in 12 weeks. Altogether, this study confirmed that BV-engineered ASCs co-expressing BMP-2/SDF-1 could synergistically stimulate the ASCs osteogenesis in vitro and improve the calvarial bone healing in vivo.