Notch signaling during chondrogenesis of human bone marrow stem cells

Notch signaling is an important mechanism involved in early development which helps to determine the differentiation and fate of cells destined to form different tissues in the body. Its role in the differentiation of adult stem cells, such as those found in bone marrow is much less clear. As there is great interest in the potential of human bone marrow stem cells (hMSC) as a source of cells for the repair of articular cartilage and other tissues, it is important to understand if Notch signaling promotes or suppresses differentiation. Using primary human bone marrow stem cells (hMSC) in 3D cell aggregate culture a new study has investigated the expression of the canonical Notch pathway genes during chondrogenesis and showed that the Notch ligand, Jagged1 (JAG1) sharply increased in expression peaking early in differentiation. A Notch target gene, HEY1, was also expressed with a temporal profile, which closely followed the expression of JAG1 and this preceded the rise in type II collagen expression that characterized chondrogenesis. The JAG1 mediated Notch signaling was shown with a Notch inhibitor (DAPT) to be necessary for chondrogenesis, as inhibition days 0-14, or just days 0-5, blocked chondrogenesis, whereas Notch inhibition days 5-14 did not. In further experiments Notch signaling was shown to be critical for full chondrogenesis, as adenoviral hJAG1 transduction of hMSCs, which caused continuous expression of JAG1 and sustained Notch signaling, completely blocked chondrogenesis. In these cultures there was inhibited production of extracellular matrix and failure to differentiate was interpreted as the retention of the hMSC in a pre-chondrogenic state. The results in this study thus showed that JAG1 mediated Notch signaling in hMSC was necessary to initiate chondrogenesis, but must be switched off for chondrogenesis to proceed and it will be important to establish if this is a mechanism common to all chondrocyte differentiation.