Intercellular communication upon mechanical stress stimulation in epithelial morphogenesis – CellCOMM

How three dimensional tubular or branched structures are formed from an epithelial sheet is a fundamental open question in developmental and regenerative biology. The proposed project aims to decipher the role of local mechanical stress propagation as a mechanism of intercellular communication and spatio-temporal coordination within branching epithelial tissues.
Branching of many organs is associated with local increase in proliferation within the epithelium. Rapid advances in biochemistry and molecular biology have led to an extended understanding of tissue patterning from the perspective of genetic programming and chemical signalling. However, in vitro experiments suggest that gradients of morphogens are insufficient to provide spatial coordination since in such cultures proliferation patterns arose despite the global distribution of growth factors. More importantly, patterns of proliferation were not observed until branches had already formed suggesting that other compensatory mechanisms exist. Despite recent advances, we still know little on the role of mechanics in developmental processes and the spatio-temporal coordination of various biological events.
Recent works provided evidence for a long-distance mechanosensing, demonstrating that cells within epithelial sheets are capable to adjust to local changes for example in substrates rigidity at the tissue scale level by altered tension at cellular junctions. We have recently proposed first quantitative approach to measure tissue stress within 3D cellular aggregates (Dolega et al, Nature Comm 2017). Our results confirm that mechanical stress can propagate through multicellular structures and locally change biological state of cells. Following these evidences, our hypothesis is that local mechanical stress generated by epithelial sheet deformation during morphogenetic processes induces patterns of cell proliferation within epithelial sheets by mechanical signal propagation.
In the CellCOMM project we propose:
1) To design and develop a novel technology that enables precise spatio-temporal control of mechanical stimulation within adherent epithelial sheets, allowing subsequent mechanistic dissection of the role of the local stress in initiating and driving tissue-patterning.
2) To precisely correlate mechanical stress propagation and the consequent biological response in the function of stimulation magnitude and frequency. We will determine the characteristic scale at which mechanical forces potentially play role in morphogenesis. Additionally, we will determine the impact of mechanical stress on initiation of branching morphogenesis by creating a pseudo-3D model enabling mechanically stimulated cells to organize in 3D.