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Potentiality of mesenchymal stem cells with ex vivo gene therapy for osteochondral defect in arthritis

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Ex vivo gene therapy includes culture-expansion of pluripotent stem cells, genetic manipulations in vitro and reimplantation into a recipient. This cell-mediated gene transfer with adenoviral vectors may be safer than in vivo techniques since it avoids the inoculation of viral particles into the body. Previous studies have shown that the transduced cells can contribute to bone and cartilage regeneration when osteoprogenitor cells or mesenchymal stem cells were used as the carrier to transfer the BMP-2 protein. However, these studies did not reveal that these infected cells continue to secrete the transduced protein. Also, the fate of these cells remained unknown, whether they could become incorporated into host tissue and differentiated into cartilage and bone. To investigate these parameters, we constructed an adenoviral vector encoding the myc epitope-tagged BMP-2 gene (AdBMP-2Myc). Rat bone marrow cells (rBMCs) transduced with AdBMP-2Myc produced biologically active BMP-2 protein, which was confirmed by Western blot analysis and alkaline phosphatase assay. Ex vivo studies using rBMCs infected with AdBMP-2Myc and implanted into the hindlimbs of SCID mice demonstrated orthotopic bone formation by 1 week and greater consolidation at the later time periods. Immunohistological analysis revealed that the Myc-positive cells differentiated into chondrocytes and became introduced into the bone during the endochondral ossification process. The different distribution of BMP-2 and Myc-positive cells suggested that exogenous BMP-2 protein, delivered by infected rBMCs, can induce endogenous BMP-2 protein expression and bone formation from host osteoprogenitor cells. Our study indicated that osteprogenitor cells can be utilized as the delivery vehicle for therapeutic osteochondral inductive genes, and their transduced cells themselves can develop into terminal differentiated mesenchymal tissues, like cartilage and bone. Therefore, the cell selection is critical when using an ex vivo gene therapy strategy, and this adenoviral construct is useful for the evaluation of cell-tracing experiments to determine the distribution of the secreted protein.

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Inoue, H., Abe, N. & Lieberman, J. Potentiality of mesenchymal stem cells with ex vivo gene therapy for osteochondral defect in arthritis. Arthritis Res Ther 5, 163 (2003) doi:10.1186/ar964

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Keywords

  • Mesenchymal Stem Cell
  • Adenoviral Vector
  • Endochondral Ossification
  • Osteochondral Defect
  • Osteoprogenitor Cell