Abstract
Mesenchymal stem cells (MSC) may have great potential for cell-based therapies of osteoarthritis. However, after injection in the joint, only few cells adhere to defective articular cartilage and contribute to cartilage regeneration. Little is known about the molecular mechanisms of MSC attachment to defective articular cartilage. Here, we developed an ex vivo attachment system, using rat osteochondral explants with artificially created full-thickness cartilage defects in combination with genetically labeled MSC isolated from bone marrow of human placental alkaline phosphatase transgenic rats. Binding of MSC to full-thickness cartilage lesions was improved by serum, but not hyaluronic acid, and was dependent on the presence of divalent cations. Additional in vitro tests showed that rat MSC attach, in a divalent cation-dependent manner, to collagen I, collagen II, and fibronectin, but not to collagen XXII or cartilage oligomeric matrix protein (COMP). RGD peptides partially blocked the adhesion of MSC to fibronectin in vitro and to cartilage lesions ex vivo. Furthermore, the attachment of MSC to collagen I and II in vitro and to cartilage lesions ex vivo was almost completely abolished in the presence of a β1 integrin blocking antibody. In conclusion, our data suggest that attachment of MSC to ex vivo full-thickness cartilage lesions is almost entirely β1 integrin-mediated, whereby both RGD- and collagen-binding integrins are involved. These findings suggest a key role of integrins during MSC attachment to defective cartilage and may pave the way for improved MSC-based therapies in the future.
Highlights
Cell therapies or cell-based gene therapies with adult multipotent mesenchymal stem cells (MSC) may have a large impact on the treatment of many diseases of various organ systems in the future.[1]
The key findings in our study were (1) that serum improves MSC attachment to cartilage lesions, (2) that divalent cations are essential for binding of MSC to full-thickness cartilage lesions as well as for MSC binding to collagen I, collagen II, and fibronectin, (3) that b1 integrin blocking antibodies fully block binding of rat MSC to collagen I and collagen II, but only partially inhibit binding to fibronectin, and (4) that RGD peptides partially block the adhesion of MSC to fibronectin in vitro and to cartilage lesions ex vivo
Our data suggest that both RGD- and collagen-binding integrins are involved in the attachment of MSC to full-thickness articular cartilage lesions
Summary
Cell therapies or cell-based gene therapies with adult multipotent mesenchymal stem cells (MSC) may have a large impact on the treatment of many diseases of various organ systems in the future.[1] One of the typical diseases in which MSC-based therapies may hold great promise is osteoarthritis (OA). OA is the most common age-related form of arthritis with prevalence for the knee and hip joint. The initiation of the disease is triggered by genetic disposition, single major trauma, a series of microtraumas, or strenuous exercise.[2] The few differentiated chondrocytes within the articular cartilage have only minimal regeneration potential,[3] leading to a poor prognosis for patients suffering from OA.[4].
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