Abstract
The repair of focal articular cartilage defects remains a problem. Combining gene therapy with tissue engineering approaches using bone marrow-derived mesenchymal stem cells (MSCs) may allow the development of improved options for cartilage repair. Here, we examined whether a three-dimensional fibrin-polyurethane scaffold provides a favorable environment for the effective chondrogenic differentiation of human MSCs (hMSCs) overexpressing the cartilage-specific SOX9 transcription factor via recombinant adeno-associated virus (rAAV) -mediated gene transfer cultured in a hydrodynamic environment in vitro. Sustained SOX9 expression was noted in the constructs for at least 21 days, the longest time point evaluated. Such spatially defined SOX9 overexpression enhanced proliferative, metabolic, and chondrogenic activities compared with control (reporter lacZ gene transfer) treatment. Of further note, administration of the SOX9 vector was also capable of delaying premature hypertrophic and osteogenic differentiation in the constructs. This enhancement of chondrogenesis by spatially defined overexpression of human SOX9 demonstrate the potential benefits of using rAAV-modified hMSCs seeded in fibrin-polyurethane scaffolds as a promising approach for implantation in focal cartilage lesions to improve cartilage repair.
Highlights
Articular cartilage is the tissue that allows for a smooth, frictionless weightbearing surface in articulating joints
The results demonstrate that human MSCs (hMSCs) can be modified via recombinant adeno-associated virus (rAAV) to overexpress SOX9 over an extended period of time within PU scaffolds, leading to an improved cell chondrogenic differentiation in such an environment relative to control vector treatment, as a promising future approach for the treatment of sites of cartilage injury
Human adult mesenchymal stem cell aggregate cultures were first transduced with the candidate recombinant adeno-associated virus FLAG-tagged SOX9 vector compared with control treatment in order to evaluate whether rAAV was capable of promoting the overexpression of the transcription factor upon seeding of the modified cells in fibrin-polyurethane (PU) scaffolds and cultivation in hydrodynamic culture conditions in chondrogenic differentiation medium over time in vitro (Figure 1)
Summary
Articular cartilage is the tissue that allows for a smooth, frictionless weightbearing surface in articulating joints. While improved clinical parameters were frequently reported upon application of MSCs, without adverse reactions, such approaches far led to the production of a repair tissue of lesser quality relative to the original hyaline cartilage. To overcome such limitations, gene transfer combined with tissue engineering may allow to provide reparative signals in a spatially defined fashion [15,16] to increase the chondrogenic capacities of MSCs aiming at enhancing focal cartilage repair [17,18]
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