Physical basis of Collective Mechano-Transduction: Bridging cell decision-making to multicellular self-organisation

Project Information

PhysCoMeT

Grant agreement ID: 101041418

DOI

10.3030/101041418

EC signature date 15 February 2022

Start date 1 July 2022

End date 30 June 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 499 381,00

EU contribution

€ 1 499 381,00

Coordinated by

KOBENHAVNS UNIVERSITET
Denmark

Periodic Reporting for period 1 - PhysCoMeT (Physical basis of Collective Mechano-Transduction: Bridging cell decision-making to multicellular self-organisation)

Reporting period: 2022-07-01 to 2024-12-31

Summary of the context and overall objectives of the project

Everywhere in our body, cells are exposed to mechanical forces. The forces come in various forms from the cell environment. For example, cells lining outer layers of human organs experience compression or tension due to the geometry of the organ. A rapidly expanding body of evidence is establishing that cells sense and respond to the mechanical cues from their environment, challenging the current genetic/molecular- centric view of cellular decision-making.
The connection between mechanical forces and cell response is the process of mechanotransduction, in which mechanical forces activate biochemical signaling by changing the concentration of certain proteins inside the cells. Therefore, mechanical forces act as messengers, informing cells of changes in microenvironment and instructing them to react.
With this ERC grant, I combine physical modeling with biological experiments, to study the role of mechanical forces in spreading of cell groups and to formulate an integrated view of cellular decision-making, which incorporates mechanics as an integral part of the process.
I expect the outcomes of this research to offer fundamentally new capabilities to mechanically guide multicellular trajectories in space and time with enormous potential both for improved medical interventions and for new strategies in regenerative medicine in which mechanical signals will be used to direct the repair of tissues, organs, and human body parts that have been damaged by trauma or disease.
To receive this ERC Starting Grant is an important achievement for me as it signifies a commanding presence in the international research community and allows to extend my group’s theoretical and computational work further into experimental research as well.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Our initial hypothesis, based on the existing literature was that activation of the mechanosensor (YAP) signal is related to the projected cell area in cell layers. However, unlike the established literature for single cells and dilute conditions, we have found that in cell layers that are most relevant for real tissues, none of the established results in the literature could determine the signal activation. Instead, in the multicellular context, we have found that the local packing fraction is seemed to be the universal determinant of signal activation overriding all the previously hypothesised effects. As such this part has led to an unexpected outcome. Building on this finding, we have formulated an active Ising model for Mechanotransduction connecting signal activation to local packing fraction, which has led to interesting results such as percolation of active clusters within cell layers, that, remarkably, we have now also found experimental evidence for it as well. We are currently preparing a manuscript for submission base don these results. Moreover, we have established a 3D computational framework for studying cell layers that has led to new predictions on the mechanical hotspots in multicellular assemblies as well as physics of solid-to-fluid transition in active cell layers that are now published in eLife and Interface journals, respectively. Moreover, we are now preparing a manuscript for submission where we present a first experimental evidence of reliably predicting Mechanotransduction hotspots from flow trajectories of cells using the concept of Lagrangian Coherent Structures. As such the main outcomes so far can be summarized as:
scientific discoveries, theories, methodologies, products
- Generic theory of p-atics on curved surfaces: developed in collaboration with colleagues at Harvard, we introduced a theoretical formalism for studying generically ordered active matter (applicable to various kinds of biollogical cells that exhibit different kinds of order) on gurved surfaces (J. Phys. Cond. Matter 2023, PRE 2024).
- State-of-the-art three-dimensional model of cell monolayers for studying inherently 3D processes such as cell elimination (eLife 2023)
- Uncovering the nature of solid-to-fluid transition in cell monolayers (J. R. Soc. Interface 2024)
- Mechanics of cell intercalation during morphogenesis in combined experiments and modeling (Nature Comm. 2022)
- Elasticity effect on stress localization in cells (Soft Matter 2023)
- Cell segmentation-tracker, a module to ease, automate and improve the process of biological cell segmentation, tracking and subsequent (mostly biophysical) statistical analysis. publicly available on GitHub GitHub Link
- First experimental evidence of conformal invariance in living matter including cell monolayers and bacterial colonies (currently in revision at Nature Physics)
- Experimental and numerical unveiling of how forces dictate live versus dead fate of eliminated cells (currently under revision at Nature Physics)
- Experimental and numerical unveiling of how forces determine outcomes of cellular competition (currently under revision at Nature Materials)

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

As discussed under Main Achievements finding local packing fraction to override all the known determinants of YAP activation was unplanned, unexpected, and most likely challenging the current consensus in the field that is based on single cell studies. The other unplanned finding was the evidence of conformal symmetry and the fact that it is preserved among very different cell types. This is expected to also be transformative in the field as it opens up studying cells to new tools from conformal field theories that have been organically developed for classic condensed matter systems. It is also very surprising that confirmation of such fundamental physics ideas comes from biology rather than the original systems they were designed for. In addition, we expect that our newest finding, currently under preparation, that we can predict Mechanotransduction hotspots from cell trajectories will present a significant advancement in the biophysics field, with potential applications extending to very different biological systems.