Cell-sheet technology combined with a thienoindazole derivative small compound TD-198946 for cartilage regeneration

Articular cartilage is a permanent tissue, with poor self-regenerative capacity. Consequently, a tissue engineering approach to cartilage regenerative therapy could greatly advance the current treatment options for patients with cartilage degeneration and/or defects. A successful tissue engineering approach would require not only induction of chondrogenic differentiation, but also suppression of subsequent endochondral ossification and chondrocyte dedifferentiation. We previously reported that direct injection of the thienoindazole derivative, TD-198946, into the knee joints of mice halted the progression of osteoarthritis; the compound induced chondrogenic differentiation without promoting endochondral ossification. In the present study, we applied TD-198946 to a cell-based cartilage reconstruction model, taking advantage of the cell-sheet technology. Cartilaginous cell-sheets were generated by culturing mouse and canine costal chondrocytes and human mesenchymal stem cells with TD-198946 on temperature-responsive dishes. The transplanted cell-sheets were then successfully used to promote the reconstruction of permanent cartilage, with no evidence of chondrocyte hypertrophy in the knee articular cartilage defects created in mice and canines. Thus, TD-198946 is a promising candidate for cell-based cartilage reconstruction therapies, enabling us to avoid any concern surrounding the use of scaffolds or cytokines to stimulate regeneration.