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  • Title: Metabolic activities and chondrogenic differentiation of human mesenchymal stem cells following recombinant adeno-associated virus-mediated gene transfer and overexpression of fibroblast growth factor 2.
    Author: Cucchiarini M, Ekici M, Schetting S, Kohn D, Madry H.
    Journal: Tissue Eng Part A; 2011 Aug; 17(15-16):1921-33. PubMed ID: 21417714.
    Abstract:
    The genetic manipulation of bone marrow-derived mesenchymal stem cells (MSCs) is an attractive approach to produce therapeutic platforms for settings that aim at restoring articular cartilage defects. Here, we examined the effects of recombinant adeno-associated virus (rAAV)-mediated overexpression of human fibroblast growth factor 2 (hFGF-2), a mitogenic factor also known to influence MSC differentiation, upon the proliferative and chondrogenic activities of human MSCs (hMSCs) in a three-dimensional environment that supports chondrogenesis in vitro. Prolonged, significant FGF-2 synthesis was noted in rAAV-hFGF-2-transduced monolayer and aggregate cultures of hMSCs, leading to enhanced, dose-dependent cell proliferation compared with control treatments (rAAV-lacZ transduction and absence of vector administration). Chondrogenic differentiation (proteoglycans, type-II collagen, and SOX9 expression) was successfully achieved in all types of aggregates, without significant difference between conditions. Most remarkably, application of rAAV-hFGF-2 reduced the expression of type-I and type-X collagen, possibly due to increased levels of matrix metalloproteinase-13, a key matrix-degrading enzyme. FGF-2 overexpression also decreased mineralization and the expression of osteogenic markers such as alkaline phosphatase, with diminished levels of RUNX-2, a transcription factor for osteoblast-related genes. Altogether, the present findings show the ability of rAAV-mediated FGF-2 gene transfer to expand hMSCs with an advantageous differentiation potential for future, indirect therapeutic approaches that aim at treating articular cartilage defects in vivo.
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