Notch Signaling Regulates the Chondrogenic Potential of Both Articular Chondrocytes and Their Progenitors During Expansion

Articular cartilage has a limited capacity for self-repair and clinical approaches to cartilage regeneration are needed. The only such approach developed to date involves an expansion of primary autologous chondrocytes in culture, followed by their reimplantation into a cartilage defect. However, because of the formation of fibrocartilage instead of hyaline cartilage, the outcome is often not satisfactory. It happens due to the de-differentiation of chondrocytes during the expansion step. Indeed, articular chondrocytes are non-proliferative and require partial or complete dedifferentiation before actively proliferating. In recent years stem/progenitor cells in articular cartilage (artSPCs) have been described. These cells maintain their own population and renew articular cartilage in sexually mature mice. artSPCs can, theoretically, be superior to chondrocytes, for repairing damaged cartilage. Accordingly, here, we searched for conditions that allow rapid expansion of both artSPCs and chondrocytes with simultaneous preservation of their ability to form hyaline cartilage. Among the modulators of Wnt, Notch, and FGF signaling and of cell adhesion screened, only fibronectin and modulators of the Notch pathway promoted the rapid expansion of artSPCs. Surprisingly, both inhibition and activation of the pathway had this effect. However, only inhibition of Notch during expansion facilitated the chondrogenic potential of both artSPCs and primary chondrocytes, whereas activation of this pathway abrogated this potential entirely. This effect was the same for murine and human cells. Our present observations indicate that Notch signaling is the major regulator of the chondrogenic capacity of both artSPCs and chondrocytes during their expansion.

Automated summary

Articular cartilage has limited ability to self-repair, and clinical approaches to cartilage regeneration are necessary. The current method involves expansion of autologous chondrocytes followed by reimplantation, but the outcome is often unsatisfactory due to dedifferentiation. In recent years, articular stem/progenitor cells (artSPCs) have been discovered, which have the potential to repair damaged cartilage. This study found that modulation of the Notch pathway during expansion facilitated chondrogenic potential of artSPCs and chondrocytes, while activation of the pathway abrogated this potential.