TENDONTOBONE · The mechanisms that underlie the development of a tendon-bone attachment unit

We walk, run and jump using the complex and ingenious musculoskeletal system. It is therefore puzzling that although each of its components has been extensively studied, research of the musculoskeleton as an integrated system and, in particular, of its assembly has been scarce. In recent years, studies conducted in my lab have demonstrated the centrality of cross regulation between musculoskeletal tissues in skeletogenesis. These works have provided me with the inspiration for a revolutionary hypothesis on the way tendons connect to bones, along with sufficient preliminary data on which to base it.The critical component in the assembly of the musculoskeleton is the formation of an attachment unit, where a tendon is inserted into a bone. Instead of two tissues that attach to each other, my novel hypothesis suggests that the entire attachment unit originates from a single pool of progenitor cells, which following differentiation diverges to form a tendon attached to cartilage.With the support of the ERC scheme, I will uncover the previously uncharacterized cellular origin of the attachment unit and the genetic program underlying its development. The attachment unit is a compound tissue, as it is composed of chondrocytes at one end and of tenocytes at the other end. We will investigate the mechanisms that facilitate in situ differentiation of mesenchymal progenitor cells into two distinct cell fates, under one defined niche. In addition, I will identify the contribution of both mechanical stimuli and molecular signals to the development of the attachment unit.The ultimate goal of this program is to provide a complete picture of attachment unit development, in order to promote understanding of musculoskeletal assembly. The acquired knowledge may provide the basis for new therapies for enthesopathies, through tissue engineering or repair.