Directing engineered tissue fate by modulating Notch signalling
The Notch cell-to-cell signalling pathway is a powerful cue to direct cell fate. Defects in various Notch proteins lead to a spectrum of cardiovascular diseases, ranging from valve calcification to infarcts of small arteries. All of these diseases are related to the cells taking a wrong turn when deciding on their fate.
Since the Notch pathway is such a powerful cue and highly dose-dependent, cells use multiple mechanisms of regulation to control the amount of active signalling. These mechanisms include transcription, translation, post-translational modifications, trafficking, endocytosis, recycling and degradation regulation.
To be able to use the Notch pathway to direct the fate of tissue-engineered heart valves, we will study the cross-talk of the Notch pathway with the hemodynamic forces that the implants will be exposed to in the heart valves. We work with shear and/or strain models to discover effects on Notch regulation, Notch activity, and ultimately cell fate.
This knowledge will be implemented by incorporating activators or inhibitors of Notch signalling in the scaffolds we use for tissue-engineering. With this we aim to direct the tissue generating cells to mimic healthy tissue as closely as possible.