Mechanobiology of Plastic Adaptation in Retinal Pigment Epithelium

• Applicant: Dr. Jacopo Di Russo
• Subject Area: Cell Biology ; Biophysics
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505891634

Epithelial cells are highly interconnected and create a mechanical and biochemical continuum able to accomplish specific tissue functions. This is particularly challenging in postmitotic epithelia, where the natural cell loss is compensated by dynamic cellular reconfiguration to maintain tissue integrity. The postmitotic retinal pigmental epithelium (RPE), owing to the ability to tolerate monolayer defects, ensures the functionality of the retina in ageing with cellular deformation and multinucleation. In monolayers, cell morphology and organisation indicate tensions and pressures within the sheet, with preferred stable configurations of an ideal honeycomb-like arrangement. In the area of the highest density of photoreceptors, the RPE monolayer shows a homogeneous tiling consisting of pentagonal- hexagonal-shaped cells. This homogenous tiling becomes highly disorganised in ageing and disease, featuring cytoskeletal defects and increased heterogeneity of cell shapes and sizes. This adaptive strategy, here defined as plastic adaptation, may affect the monolayer mechanics and thus the fundamental function of the tissue. Using a murine model, we propose first to characterise and quantify age-related changes of monolayer organisation and define the molecular and biophysical nature of local tiling defects. Secondly, we aim to establish an in vitro model to study the mechanobiology of plastic adaptation using stem cell-derived human cells. With nanoindentation, traction force and monolayer stress microscopy, we will evaluate the mechanical shift resulting from the accumulation of defects in the monolayers. Finally, the use of specific hydrogels as culture substrates will allow the dissection of the role of extracellular matrix biochemical, mechanical, and topographical changes for RPE monolayer plastic adaptation.

• DFG Programme: Research Grants