Abstract
Cost-effective, expedited approaches for bone regeneration are urgently needed in an ageing population. Bone Morphogenetic Proteins (BMPs) stimulate osteogenesis but their efficacy is impeded by their short half-life. Delivery by genetically modified cells can overcome this problem. However, cell isolation and propagation represent significant obstacles for the translation into the clinic. Instead, complete gene activated fragments of adipose tissue hold great potential for bone repair. Here, using an in-vitro culture system, we investigated whether adenoviral transduction with human BMP-2 can promote osteogenic differentiation within adipose tissue fragments. Osteoinduction in adipose tissue fragments was evaluated by quantitative reverse transcriptase polymerase chain reaction, immunohistology and histomorphometry. BMP-2 transduced adipose tissue synthesized BMP-2 protein over 30 days peaking by day six, which significantly promoted osteogenic differentiation as indicated by increased calcium depositions, up-regulation of bone marker genes, and bone-related protein expression. Our results demonstrate that cells within adipose tissue fragments can differentiate osteogenically after BMP-2 transduction of cells on the surface of the adipose tissue. BMP-2 gene activated adipose tissue represents an advanced osteo-regenerative biomaterial that can actively contribute to osteogenesis and potentially enable the development of a novel, cost-effective, one-step surgical approach to bone repair without the need for cell isolation.
Highlights
Adipose tissue is an abundant source of adult mesenchymal stem cells with emerging promise in the field of tissue engineering and regenerative research
Can an osteogenic environment stimulate an osteogenic response within adipose tissue fragments and can the transduction with the human BMP-2 (hBMP-2) gene enhance the osteogenic response within the adipose tissue or does the transduced tissue merely serve as a morphogen reservoir generating osteogenic growth factors, which stimulate the migration and osteogenic differentiation of cells from the surrounding tissue of a bone defect? If the role of the adipose tissue in bone repair was limited to growth factor production and stem cell recruitment from the environment of the lesion, it would make sense to focus on the development of improved drug delivery systems rather than cellular implants and therapeutics
Instead of utilizing biomaterials combined with morphogens that have so far fallen short of achieving the necessary bone formation clinically[26,27,28], genetically altered tissues or stem cells might have the potential to transform directly into the designated tissue types
Summary
Adipose tissue is an abundant source of adult mesenchymal stem cells with emerging promise in the field of tissue engineering and regenerative research. Whilst various gene therapy techniques have been developed ever since its discovery in 197216, the most promising approach for tissue repair so far is the ex vivo method[17,18,19] This procedure involves the transfer of exogenous cDNA to prior isolated cells in vitro and the subsequent implantation of the genetically modified cells back into a tissue lesion. The goal of this study was to explore the effect of hBMP-2 transduction on fragments of subcutaneous adipose tissue from rats in vitro, characterize the hBMP-2 protein expression profile after the application of the adenoviral vector to tissue fragments and evaluate whether bone induction within the transduced adipose tissue can be elicited By better defining this process, results from this study could provide deeper insight into the repair mechanisms using gene-activated tissue grafts and contribute to the development of new expedited gene therapy approaches facilitating endogenous bone repair
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