Elucidating the role of mechano-signalling feedback in dense cellular collectives

Collective tissue behaviour is inherently a multiscale phenomenon that is governed by complex biochemical and mechanical processes occurring simultaneously at the molecular (L1), cellular (L2), and tissue (L3) scales. Although much research has been devoted to elucidating biological processes at each separate scale [1,2], there is still no generic framework that describes multicellular self-organisation at all relevant scales. The aim of this project is to bridge this gap by developing a coarse-grained multi-scale model (L1-L3) for cellular collectives, in particular for collective cell jamming and unjamming at confluency. The key rationale behind our approach is to map the biomolecular complexity of cells (L1) to effective cellular ‘material properties’ (L2), for which we can then harness the power of physics to make quantitative predictions of emergent multiscale self-organisation (L3). A crucial ingredient in our framework—fundamentally lacking in most physical approaches—is the presence of mechanochemical signalling feedback pathways, which can change dynamically and can be regulated at different scales. To model this, we will build upon the celebrated active vertex model (T9), pioneered by Henkes and co-workers, and introduce feedback pathways as explicitly dynamic (i.e. non-constant) model parameters governing the cell shapes and (active) stresses [3]; these can vary dynamically due to the presence of neighbouring cells. In parallel, we will use active mode-coupling theory (T2), developed by the Janssen group [4], to predict and understand how, on a coarser-grained level, the feedback-induced structural changes affect the jamming/unjamming dynamics of the cellular collective. These theory predictions can be directly validated against the in-silico vertex model.

Our combined theory (T2) and in-silico multiscale model (T9) will allow us to predict the collective dynamics emerging from mechanochemical coupling, and hence infer the key properties at the micro- and mesoscale (L1-L2) that shape collective behaviour at the macroscale (L3). In particular, we will elucidate how dynamically changing active stresses and cell shapes, arising from implicit signaling with neighboring cells, affect the emergent dynamics of the cellular collective. While our main focus will be on elucidating the multiscale mechanisms that govern collective jamming/unjamming behaviour, the new model may also be applicable to other collective cell phenomena.

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[1] De Belly, H, et al. (2022) Nat Rev Mol Cell Biol 23:465 [2] Hannezo, E, & Heisenberg, C-P (2019) Cell 178:12 [3] Sknepnek, R, et al (2023), Elife 12, e79862 [4] Debets, VE, & Janssen, LMC. (2023) J Chem Phys 159:014502