Mechanobiology studies the response of cells and tissues to the mechanical environment during various biological processes. Although major advances have made it possible to observe the behavior of cells in space in vitro, observations are often qualitative, as it is very difficult to quantify the stresses, strains and mechanical parameters associated with specific cellular behavior. Mechanical and mathematical modeling of cell behavior is therefore fundamental to exploring a large number of scenarios with reduced time and cost compared to laboratory experiments. What's more, such an approach also makes it possible to test conditions that are not experimentally feasible.
In this project, we focus on cell migration under confinement, a mechanobiological process that can be observed during embryogenesis, bone remodeling, immune response or tumor invasion. In these different biological processes, cells migrate through subcellular (10-30 µm wide) or subnuclear (2-10 µm wide) pores. The nucleus, the largest and most rigid cell organelle, plays a critical role in confined environments, as it can inhibit and progressively slow down cell migration. In addition, the components of the nucleus (chromatin and the elements that make up the nucleus envelope) and the links that bind the nucleus to the cell's cytoskeleton have a strong impact on the mechanical properties of the cell and nucleus, and consequently on cell migration.
Our main objective is to study the influence of the mechanical properties of the nucleus and nucleo-cytoskeletal links on migration in a confined environment. We will use biological and biophysical experimental approaches to modulate cellular and nuclear components and quantify the effect induced on the mechanical properties and migratory capacities of cells. Controlled modulation of i) heterochromatin, ii) nucleus-cytoskeleton links, and iii) the cytoskeleton will enable us to determine how each component individually contributes to cell properties. We will combine the experimental results with a numerical multiphysics model developed as part of the project. This model will integrate both the molecular and mechanical aspects of migration in a confined environment. It will be fed by experimental data and validated by comparing its predictions with measurements obtained with the different experimental approaches used in the project (core rheology using optical tweezers, cell rheology using microfluidics, quantitative cell migration). Once validated, the model will be used to explore scenarios that are difficult or time-consuming to access in vitro.
For example, we can modulate at will the mechanical properties of the cell or its individual elements, the size of the nucleus within the cell, or the degree of confinement (structure or geometry of the external environment). The model will establish the correlation between the stress-strain relationship of the cell and its components and its ability to migrate under confinement, enabling us to determine the mechanical conditions required to favor or hinder confined migration. On the one hand, our approach will generate new fundamental knowledge, namely a better understanding of the mechanical characteristics of the nucleus and its links with its cellular environment as key factors in confined migration. On the other hand, it will also pave the way for the development of innovative diagnostic and prognostic tools to identify pathological cells.
The project is funded by the ANR (ANR-24-CE45-0690).