Local administration of TGFβ-1/VEGF165 gene-transduced bone mesenchymal stem cells for Achilles allograft replacement of the anterior cruciate ligament in rabbits

Abstract

Graft remodeling following anterior cruciate ligament (ACL) reconstruction requires a long period of recovery before it is capable of withstanding physiological loads. Graft revascularization is extremely important in the remodeling process. In ACL reconstruction, the local administration of vascular endothelial growth factor (VEGF) significantly increased revascularization of the graft, but did not significantly affect the mechanical properties of the graft after implantation (Ju et al., 2006; Yoshikawa, et al., 2006). Our previous studies showed that transforming growth factor-β1 (TGFβ1) could promote improvements in mechanical strength in Achilles tendon regeneration, by regulating collagen type I and type III synthesis, cross-link formation, and matrix-remodeling (Hou et al., 2009). The current study aims to investigate whether the co-expression of TGFβ1/VEGF(165) could beneficially affect the remodeling of ACL grafts. Bone marrow-derived mesenchymal stem cells (BMSCs), transfected with an adenoviral vector encoding TGFβ1, VEGF(165) or TGFβ1/VEGF(165), were surgically implanted into experimental ACL grafts, with non-transfected cells as a control. HE and toluidine blue staining, vascular number, and biomechanical features were analyzed at 3, 6, 12, and 24 weeks after surgery. The results suggest that TGFβ1 expression, in the TGFβ1/VEGF(165)-transfected BMSCs, could accelerate the remodeling of the reconstructed ligament. The cross-talk between TGFβ1 and VEGF(165) has positive consequences, as TGFβ1/VEGF(165)-transfected BMSCs significantly promoted angiogenesis of the reconstructed ligament at 3, 6, 12 weeks, with the best mechanical properties being achieved at 24 weeks. Furthermore, co-expression of these genes is more powerful and efficient than single gene therapy.