Stemming cartilage degeneration: Adult mesenchymal stem cells as a cell source for articular cartilage tissue engineering

Rocky S. TuanDegenerative joint diseases such as osteoarthritiscause pain and compromise mobility, thus posing asignificant disease burden. Articular cartilage, the load-bearing tissue of the joint, has limited potential forrepair and regeneration. An attractive approach is todevelop engineered cartilage constructs for the repair oflarge chondral defects (1). Cartilage tissue engineeringrequires 3 components: cells, scaffold, and environment.Adult stem cells, specifically mesenchymal stem cells(MSCs), are often considered a promising candidate cellsource because of the ease with which they can beisolated and expanded and their chondrogenic differen-tiation capabilities.MSCs are isolated from many adult tissue types,such as bone marrow, skin, muscle, and trabecular bone,and are characterized by their ability to undergo exten-sive self-renewal in vitro and to assume multilineagedifferentiation, including osteogenesis, chondrogenesis,and adipogenesis (2). Commonly selected by differentialsubstrate adhesion, MSCs exhibit surface epitopes suchas Stro1 and CD105, although no MSC-specific molec-ular marker(s) have been identified. The chondrogenicactivity of MSCs has been demonstrated in vitro inhigh-density pellet cultures treated with transforminggrowth factor (TGF ) (3). The appearance of acartilage phenotype is accompanied by characteristichistologicfeatures,theexpressionofcartilage-associatedgenes such as types II and IX collagen as well asaggrecan and dermatopontin, and the biosynthesis ofsulfated proteoglycans. Translating the micro-scale car-tilage formation by MSCs in vitro to larger-scale carti-lage tissue engineering ex vivo and/or in vivo is a currentchallenge of musculoskeletal regenerative medicine.Developmentally, there are 2 main types of car-tilageinthemammalianskeleton(4).Transientcartilageis found in the cartilage anlage of endochondral bones,such as the growth plate of the long bones of the limbwherein mesenchymal cells condense and differentiateinto chondrocytes that proliferate, undergo maturation,hypertrophy, and apoptosis, calcify, and are then re-placed by osteoblasts. In contrast, permanent, hyalinecartilage is found on the articular joint surface. Thechallenge in using MSCs as a cell source for articularcartilage tissue engineering is therefore to maintain theMSC-derived chondrocytes in the prehypertrophic stateand prevent them from undergoing terminal differenti-ation as seen in the growth plate.Currently, the only cell-based articular cartilagerepair procedure approved by the US Food and DrugAdministration is autologous chondrocyte implantation,which was first developed by Brittberg et al (5) and iscurrently marketed as the Carticel procedure. In thisprocedure, articular cartilage plugs are surgically har-vested from the patient’s own joint, and chondrocytesare isolated and cultured as expanded chondrocytes exvivo. Subsequently, in a separate surgery, these autolo-gous cells are implanted in the form of a suspension incollagen-containing medium into the lesion site; the siteis then suture-covered with an autologous periosteumflap. More than 10,000 autologous chondrocyte implan-tation procedures have been performed, and althoughthe results are generally considered acceptable forlimited-size lesions, the effectiveness of the procedure isstill under debate (6,7). What is clearly indicated is thepotential of articular chondrocytes as a cell source forcell-based repair of cartilage defects.In comparison with autologous chondrocytes,MSCs represent a promising cell source that may beconveniently manipulated to become chondrocytes forthe purpose of cartilage repair. However, several pub-lished studies have shown that long-term pellet cul-tures of MSCs in TGF -containing chondrogenic me-dium display signs consistent with chondrocyte hyper-