Modeling tendon morphogenesis in vivo based on cell density signaling in cell culture

A mathematical model of tendon morphogenesis is presented that is consistent with the dramatic transitions seen in this tissue as it progresses from rapid growth early in development to no growth in the adult. To accomplish this change, the embryonic chick tendon is hypercellular with each cell dedicating half of its protein production to procollagen but over time, as growth subsides, the tissue gradually becomes hypocellular with each cell producing only about 1% procollagen. Making this transition from the embryonic to the adult state, forming a roughly cylindrical tissue composed of ∼90% collagen, and linking the correct muscle to the right bone, is a complex task. The proposed solution requires only two factors: an activator of growth and an inhibitor complex, composed of the activator and another molecule that modifies the activity of the activator. From a diverse set of cell culture observations, these two factors were deduced as the primary components of the mechanism that allows cells to signal their presence to their neighbors. Since cell density signaling is the principal regulator of both collagen synthesis and cell proliferation, its components should play the key role in tendon development. A mathematical model based on the changes in the concentrations of these factors with cell density correlates well with the transitions observed in vivo. Furthermore, the model predicts that in the maturing chicken there should be a high cell density region at the muscle tendon interface. Experimental observations of frozen sections of tendon from a 4 month old chicken confirm this prediction.