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Open AccessArticle

Therapeutic Effects of rAAV-Mediated Concomittant Gene Transfer and Overexpression of TGF-β and IGF-I on the Chondrogenesis of Human Bone-Marrow-Derived Mesenchymal Stem Cells

1
Center of Experimental Orthopaedics, Saarland University Medical Center and Saarland University, D-66421 Homburg/Saar, Germany
2
Department of Orthopaedic Surgery, Saarland University Medical Center and Saarland University, D-66421 Homburg/Saar, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(10), 2591; https://doi.org/10.3390/ijms20102591
Received: 25 April 2019 / Revised: 20 May 2019 / Accepted: 24 May 2019 / Published: 27 May 2019
Application of chondroreparative gene vectors in cartilage defects is a powerful approach to directly stimulate the regenerative activities of bone-marrow-derived mesenchymal stem cells (MSCs) that repopulate such lesions. Here, we investigated the ability of combined recombinant adeno-associated virus (rAAV) vector-mediated delivery of the potent transforming growth factor beta (TGF-β) and insulin-like growth factor I (IGF-I) to enhance the processes of chondrogenic differentiation in human MSCs (hMSCs) relative to individual candidate treatments and to reporter (lacZ) gene condition. The rAAV-hTGF-β and rAAV-hIGF-I vectors were simultaneously provided to hMSC aggregate cultures (TGF-β/IGF-I condition) in chondrogenic medium over time (21 days) versus TGF-β/lacZ, IGF-I/lacZ, and lacZ treatments at equivalent vector doses. The cultures were then processed to monitor transgene (co)-overexpression, the levels of biological activities in the cells (cell proliferation, matrix synthesis), and the development of a chondrogenic versus osteogenic/hypertrophic phenotype. Effective, durable co-overexpression of TGF-β with IGF-I via rAAV enhanced the proliferative, anabolic, and chondrogenic activities in hMSCs versus lacZ treatment and reached levels that were higher than those achieved upon single candidate gene transfer, while osteogenic/hypertrophic differentiation was delayed over the period of time evaluated. These findings demonstrate the potential of manipulating multiple therapeutic rAAV vectors as a tool to directly target bone-marrow-derived MSCs in sites of focal cartilage defects and to locally enhance the endogenous processes of cartilage repair. View Full-Text
Keywords: cartilage repair; MSCs; rAAV vectors; TGF-β; IGF-I cartilage repair; MSCs; rAAV vectors; TGF-β; IGF-I
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Morscheid, S.; Rey-Rico, A.; Schmitt, G.; Madry, H.; Cucchiarini, M.; Venkatesan, J.K. Therapeutic Effects of rAAV-Mediated Concomittant Gene Transfer and Overexpression of TGF-β and IGF-I on the Chondrogenesis of Human Bone-Marrow-Derived Mesenchymal Stem Cells. Int. J. Mol. Sci. 2019, 20, 2591.

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