Biology Inspired Physics at Mesoscales

Our research focuses primarily on the study of populations of interacting cells (from bacteria to epithelial cells) using physics concepts and techniques.

We therefore address fundamental problems of biology from a different perspective, complementary to the biological point of view. More specifically, we are presently involved in two main projects addressing different aspects of communication between cells, thus leading to collective behaviors: chemotaxis of bacteria and collective migration of epithelial cells. In both cases, we make use of the possibilities offered by the techniques of microfabrication: by a good control of the geometries and surface properties, we obtain highly reproducible situations with well defined boundary conditions. The microfabrication techniques we use are mainly based on soft lithography, and develop new strategies allowing such a control. These projects are quite relevant to a number of practical situations in which cells develop a collective response to natural microenvironments (biofilms, tissues, tumors…). The model systems that we develop are a first step towards the understanding of these behaviors.

Chemotaxis of bacteria

fig 1: Concentration wave of E. coli bacteria in a microchannel and details of the individual trajectories
fig 1: Concentration wave of E. coli bacteria in a microchannel and details of the individual trajectories

E. coli is not only chemotactic, i.e. this bacterium swims towards a source of attractants (food, oxygen…), it also expresses some of these attractants. This property presents some similarities with a classical physics problem: interacting particles submitted to an external field. It gives rise to complex behaviors (pattern formation, self-concentrations, phase transitions…). This out-of-equilibrium system, from the statistical physics point of view, is also at the origin of concentration waves that can be easily observed in suspensions in microchannels. We can tune several parameters (external fields, geometries of the channels…) and observe the propagation of concentration fronts (figure 1) in order to understand the rules governing the behavior of this system.

 

In the near future, we plan to study more in depth the nature of these concentration waves for instance by inserting obstacles in their way.

video 1 : Propagation of a bacteria concentration wave (E. coli) in a microchannel. velocity of the wave : 4 um/s. width of the channel 500 um. depth : 100 um

Collective migration of epithelial cells

By using an original injury-free technique developed in our group, we can release free surface to a confluent epithelium without damaging the cells (figure 2).

fig2: Représentation schématique des expériences. Le décollement du pochoir déclenche la migration des cellules.
Fig. 2 : Schematic representation of the experiments. The peeling off of the stencil triggers the migration of the cells.

Under these conditions, they spread and migrate on this newly available substrate. The cells keeping cell-cell contacts, this motility has collective properties that give rise to unusual characteristics and in particular, a strong fingering of the newly created border and the apparition of “leader” cells that have very distinct features (figure 3).

fig 3 : Migration cellulaire observée lorsque l'on libère de la surface (t=0, retrait du pochoir). A gauche : Digitation du bord de l'épithélium (largeur initiale = 400 µm). A droite : Les doigts sont précédés d'une « cellule leader » semblable à un fibroblaste
Fig.3 : Cell migration on new available substrate. Left : Fingering of the edge of the epithelium (initial width is 400 µm). Right : Fingers are preceded by a transient fibroblast-like “leader cell” (bar is 100 µm).

 

ig 4: Champ de vitesse dans un épithélium en migration obtenu par vélocimétrie par imagerie de particules. Les déplacements des cellules sont très corrélés et s'étendent sur environ 15 cellules.
Fig 4. : Velocity field in a migrating epithelium obtained by Particle Image Velocimetry. The displacements of the cells are highly correlated and extend over ~ 15 cells.

The similarity of some of these observations with multicellular clusters stemming out of epithelial tumors in vivo is an incentive to develop a tridimensional equivalent. We have started the first experiments in that direction. In all these situations, various quantities are measured from subcellular to multicellular scales (forces developed by the cells, displacements and velocity fields (figure 4), shapes or polarities…), and are correlated to the relevant biochemical signals, such as oxygen consumption or activity of small G-proteins.

This highly parallel and quantitative approach enables us to efficiently interact with theory groups in order to interpret our experiments and model these out-of-equilibrium phenomena.

 

 

Video 2 Migration of an epithelial monolayer on free surface (MDCK cells; video duration 33hr; initial wound width 400 µm)

 

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Key publications

Year of publication 2017

Duclos G., Erlenkämper C., Joanny J.-F., Silberzan P. (2016 Sep 12)

Topological defects in confined populations of spindle-shaped cells

Nature Physics : 13 : 58-62 : DOI : 10.1038/nphys3876

Year of publication 2015

Vincent Nier, Maxime Deforet, Guillaume Duclos, Hannah G Yevick, Olivier Cochet-Escartin, Philippe Marcq, Pascal Silberzan (2015 Jul 21)

Tissue fusion over nonadhering surfaces.

Proceedings of the National Academy of Sciences of the United States of America : 9546-51 : DOI : 10.1073/pnas.1501278112
Yevick HG, Duclos G, Bonnet I, Silberzan P. (2015 May 12)

Architecture and migration of an epithelium on a cylindrical wire

Proc Natl Acad Sci USA112(19):5944-9

Year of publication 2014

Deforet M, Hakim V, Yevick HG, Duclos G, Silberzan P (2014 May 6)

Emergence of collective modes and tri-dimensional structures from epithelial confinement.

Nat Commun5:3747 : DOI : 10.1038/ncomms4747
Reffay M, Parrini MC, Cochet-Escartin O, Ladoux B, Buguin A, Coscoy S, Amblard F, Camonis J, Silberzan P (2014 Apr 16)

Interplay of RhoA and mechanical forces in collective cell migration driven by leader cells

Nat Cell Biol16(4):382
G Duclos, S Garcia, H G Yevick, P Silberzan (2014 Mar 14)

Perfect nematic order in confined monolayers of spindle-shaped cells.

Soft matter : 10 : 2346-53 : DOI : 10.1039/c3sm52323c
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