Gene-Modified Adult Stem Cells Regenerate Vertebral Bone Defect in a Rat Model
- 11 August 2011
- journal article
- research article
- Published by American Chemical Society (ACS) in Molecular Pharmaceutics
- Vol. 8 (5), 1592-1601
- https://doi.org/10.1021/mp200226c
Abstract
Vertebral compression fractures (VCFs), the most common fragility fractures, account for approximately 700,000 injuries per year. Since open surgery involves morbidity and implant failure in the osteoporotic patient population, a new minimally invasive biological solution to vertebral bone repair is needed. Previously, we showed that adipose-derived stem cells (ASCs) overexpressing a BMP gene are capable of inducing spinal fusion in vivo. We hypothesized that a direct injection of ASCs, designed to transiently overexpress rhBMP6, into a vertebral bone void defect would accelerate bone regeneration. Porcine ASCs were isolated and labeled with lentiviral vectors that encode for the reporter gene luciferase (Luc) under constitutive (ubiquitin) or inductive (osteocalcin) promoters. The ASCs were first labeled with reporter genes and then nucleofected with an rhBMP6-encoding plasmid. Twenty-four hours later, bone void defects were created in the coccygeal vertebrae of nude rats. The ASC-BMP6 cells were suspended in fibrin gel (FG) and injected into the bone void. A control group was injected with FG alone. The regenerative process was monitored in vivo using microCT, and cell survival and differentiation were monitored using tissue specific reporter genes and bioluminescence imaging (BLI). The surgically treated vertebrae were harvested after 12 weeks and subjected to histological and immunohistochemical (against porcine vimentin) analyses. In vivo BLI detected Luc-expressing cells at the implantation site over a 12-week period. Beginning 2 weeks postoperatively, considerable defect repair was observed in the group treated with ASC-BMP6 cells. The rate of bone formation in the stem cell-treated group was two times faster than that in the FG-treated group, and bone volume at the end point was 2-fold compared to the control group. Twelve weeks after cell injection the bone volume within the void reached the volume measured in native vertebrae. Immunostaining against porcine vimentin indicated that the ASC-BMP6 cells contributed to new bone formation. Here we show the potential of injections of BMP-modified ASCs to repair vertebral bone defects in a rat model. Our results could pave the way to a novel approach for the biological treatment of traumatic and osteoporosis-related vertebral bone injuries.Keywords
This publication has 51 references indexed in Scilit:
- Genetically Modified Mesenchymal Stem Cells Induce Mechanically Stable Posterior Spine FusionTissue Engineering, Part A, 2010
- The Effect of Simulated Microgravity on Human Mesenchymal Stem Cells Cultured in an Osteogenic Differentiation System: A Bioinformatics StudyTissue Engineering, Part A, 2010
- A Randomized Trial of Vertebroplasty for Osteoporotic Spinal FracturesNew England Journal of Medicine, 2009
- A Randomized Trial of Vertebroplasty for Painful Osteoporotic Vertebral FracturesNew England Journal of Medicine, 2009
- Long term non-invasive imaging of embryonic stem cells using reporter genesNature Protocols, 2009
- Comparison of Reporter Gene and Iron Particle Labeling for Tracking Fate of Human Embryonic Stem Cells and Differentiated Endothelial Cells in Living SubjectsThe International Journal of Cell Cloning, 2008
- An estimate of the worldwide prevalence and disability associated with osteoporotic fracturesOsteoporosis International, 2006
- Costs and quality of life associated with osteoporosis-related fractures in SwedenOsteoporosis International, 2005
- Direct Three-Dimensional Morphometric Analysis of Human Cancellous Bone: Microstructural Data from Spine, Femur, Iliac Crest, and CalcaneusJournal of Bone and Mineral Research, 1999
- Medical Expenditures for the Treatment of Osteoporotic Fractures in the United States in 1995: Report from the National Osteoporosis FoundationJournal of Bone and Mineral Research, 1997