Cardiovascular-tissue-on-a-chip to study crosstalk between hemodynamics and cell-cell signalling in tissue engineering outcome

Cell-cell communication and the response of cells to hemodynamics are important contributors to early tissue formation and late homeostasis of tissue engineered heart valves. To be able to study these contributors and the interaction between hemodynamics and cell-cell communication, we have set up a ‘cardiovascular-tissue-on-a-chip’ model system. The chip consists of a silicon device based upon the lung- or gut-on-a-chip system, with two juxtaposed culture channels, separated by a porous membrane. This device enables independent control over 5 factors in the complex system of cell-cell communication under hemodynamics: the stretch, fluid flow shear stress, the two cell types involved and the contact interface between these two cell types (pore size and porosity).

Currently we have reconstituted a vessel wall model in this system, by culturing aortic endothelial cells and aortic smooth muscle cells in the chip. The cells are capable of cell contact based upon cell- cell signalling and visual confirmation of contacts. Hemodynamic loading induces cellular reorientation in the culture channels. In addition, the cells can be immunostained or isolated separately after culturing for further molecular analysis by qPCR to characterize transcriptional programs dependent upon hemodynamic loading and cell-cell signalling, revealing a CD31/VWF positive endothelial channel and an ACTA2 positive smooth muscle channel.

Notch signalling is a cell-cell communication pathway consisting of 4 canonical different receptors (e.g. Notch1) and 5 ligands (e.g. Jagged1). This pathway is essential in cardiovascular development, including the heart valve. Notch1 mutations can lead to bicuspid aortic valves or calcific aortic disease, whereas Jagged1 or Notch2 can cause Alagille syndrome, leading to pulmonic valve stenosis. Using a heart-valve-on-a-chip to study valvular endothelial cell-interstitial cell interactions under hemodynamic loading, we aim to further the understanding of the role of Notch signalling in heart valve development, heart valve pathology, and possibly improve tissue engineered heart valve outcomes.