Articular Cartilage Phenotype Research Articles

Cellular therapies in musculoskeletal diseases: synovial-derived mesenchymal stem cells

We have identified and characterized a population of adult human mesenchymal stem cells (MSCs) from the synovial membrane (SM) capable of differentiation to cartilage, bone, skeletal muscle, and adipose tissue in vitro. SM-MSCs can be obtained without irreversible damage, are easily expandable with limited senescence, and are phenotypically stable throughout expansion and after storage in liquid nitrogen. The use of MSCs is restricted by the as yet insufficient knowledge of the long-term stability of the repair tissue and by their tendency to differentiate towards other cell lineages. Their multilineage potential may present a risk of heterotopic tissue formation, and in vivo preclinical studies in experimental models relevant to specific clinical applications should therefore be performed. Several applications will be discussed, including autologous cell transplantation for the repair of joint surface defects, a procedure that should be carried out using cells that are stably committed to the articular cartilage phenotype, naturally resistant to vascular invasion, mineralization, and ossification. Therefore, we investigated whether human SM-MSCs can acquire in vitro the expression of the markers reported to be associated with the stable-chondrocyte phenotype, and whether this is associated with the capacity to form stable cartilage in vivo. Further exploration of the plasticity of the SM-MSCs led to the unexpected finding that they participate in the repair of skeletal muscle in two animal models. We characterized the myogenic differentiation of this cell population in a nude mouse model of skeletal muscle regeneration, and demonstrated that they contributed to myofibers and to long-term persisting functional satellite cells. When administered into dystrophic muscles of immunosuppressed mdx mice, human SM-MSCs restored, at least in part, muscle function in this mouse model of Duchenne muscular dystrophy. Many challenges remain in the area of cellular products, including product specification and quality control, and proper prospective, multi-center, randomized, clinical studies comparing this with standard treatments. There is no doubt that a clear global regulatory path is needed for the development of these novel approaches, as lack of transparency and conflicting legislation in regulation is one of the major threats preventing proper development of the field.

Expression of a stable articular cartilage phenotype without evidence of hypertrophy by adult human articular chondrocytes in vitro.

Chondrocytes that were isolated from adult human articular cartilage changed phenotype during monolayer tissue culture, as characterized by a fibroblastic morphology and cellular proliferation. Increased proliferation was accompanied by downregulation of the cartilage-specific extracellular matrix proteoglycan, aggrecan, by cessation of type-II collagen expression, and by upregulation of type-I collagen and versican. This phenomenon observed in monolayer was reversible after the transfer of cells to a suspension culture system. The transfer of chondrocytes to suspension culture in alginate beads resulted in the rapid upregulation of aggrecan and type-II collagen and the downregulation of expression of versican and type-I collagen. Type-X collagen and osteopontin, markers of chondrocyte hypertrophy and commitment to endochondral ossification, were not expressed by adult articular chondrocytes cultured in alginate, even after 5 months. In contrast, type-X collagen was expressed within 2 weeks in a population of cells derived from a fetal growth plate. The inability of adult articular chondrocytes to express markers of chondrocyte hypertrophy has underscored the fundamental distinction between the differentiation pathways that lead to articular cartilage or to bone. Adult articular chondrocytes expressed only hyaline articular cartilage markers without evidence of hypertrophy.