Researching novel microfabricated devices for the quantitative imaging of living organisms.

Overview

Our research aims at understanding how living cells interact with their environment. In particular, we are studying the cooperation between adhesion, bio-mechanical and bio-chemical signaling for the adaptation of living cells to changes in their environment. We adress these questions at various levels that include single-molecule experiments, single cell responses and multicellular system dynamics. We are developing micro- and nano-fabrication techniques as well as micromanipulation tools to control and measure the cellular responses in various situations.

Our research program includes the integration of novel microfabricated devices for the quantitative imaging of living organisms. We are conducting several research programs that specifically address the following subjects:

1. Development of novel microfabrication tools for biological research applications
2. Mechanotransduction and cellular traction forces
3. Regulation of cell-cell junctions
4. Collective behaviours of cellular assemblies

Single Cell Mechanics

In higher organisms every living cell is embedded in a complex and dynamic nanostructured environment formed by surrounding cells, extracellular matrix molecules as well as bound or soluble factors. Cell function as well as cell morphology and differentiation are strongly regulated by the elasticity and nano- microscopic topography of the environment as well as physical forces. The reason is unclear, but physical aspects of the microenvironment, especially mechanical compliance of matrix and adjacent cells, are becoming increasingly linked to gene expression and protein organization.

Sufficient substrate stiffness appears particularly important to anchorage-dependent cells, which often rely on a finite resistance to cell-generated forces in order to induce outside-in mechanical signals. Such signals feed back into cell tension, cell adhesion, posttranslational modification, protein expression, cytoskeletal organization, and even cell viability. These interactions can be studied by incorporating micro- and nanotechnology-related tools. The design of substrates based on these technologies offers new possibilities to probe the cellular responses to changes in their physical environment. The investigations of the mechanical interactions of cells and their surrounding matrix can be carried out in well-defined and near physiological conditions. In particular, this includes the transmission of forces as well as rigidity and topography sensing mechanisms.

Using these tools in combination with traditional molecular approaches, we are investigating numerous regulatory interactions between mechanical forces and biochemical signaling during cell adhesion and migration on substrates presenting various mechanical properties.

Mechanics of cell-cell junctions

How living cells are able to sense their environment and adequately respond in terms of morphology, migration, proliferation, differentiation, and survival remains one of the more puzzling issues in cell biology. This is particularly obvious in the context of embryonic development, where a specific and complex architectural organization of biological tissues is elaborated.

Embryonic cells adhere, migrate, segregate, and differentiate in a selective and coordinated fashion. As histogenesis proceeds, specific cellular junctions are formed, which contribute to the mechanical cohesion of tissues and act as platforms allowing cell communication. Furthermore dysfunctions of cell adhesion frequently lead to the loss of tissue homeostasis, having serious physiopathological consequences such as tumor development and metastasis. It is thus important to understand how, according to their physiological state and position in the embryo or tissue, cells can establish and regulate precise contacts with adjacent cells.

Conversely, one has to understand at the molecular level how cells can interpret “contact” information and transmit chemical and mechanical signals towards the cytoskeleton, the cytoplasm and the nucleus to allow an adapted cellular response. Transduction of mechanical stress is an underestimated cell adhesion-associated signal contributing to morphogenetic movements during development. For example, the traction forces developed and transmitted via integrins by cells toward the extracellular matrix and substratum have been proposed a long time ago and recently characterized in details. The mechanical stress through its effect on cell tension has high incidence on cell migration as well as survival or differentiation

In contrast, very little is known on mechano-transduction at cell-cell contacts. Our objective is to understand how cadherins will transmit mechanical stress, with the aim to better understand the mechanisms involved in the control of normal cell differentiation and its pathological dysfunctions.

tissue migration

Tissue mechanics & collective behaviors

Collective cell adhesion and movement giving rise to complex changes in multicellular tissue structures, including epithelial regeneration, the sprouting of vessels and ducts in angiogenesis and branching morphogenesis, and the deregulated invasion of cell masses during cancer progression and consecutive tissue destruction, integrate both adhesion to the ECM and to neighboring cell.

In most of the cases, mechanotransduction studies have been performed at the level of single living cell and restricted to cell‐ECM interactions. As a consequence, the mechanical processes controlling the assembly, maintenance and dissociation of adherens junctions involved in multicellular sytems remain poorly understood. During these processes, active traction forces are exerted through cell‐cell contacts that can induce different types of movements such as the sliding of neighboring cells as well as global motion of many cells, correlated with dynamical rearrangements of cell‐cell junctions.

We aim at understanding how external constraints such substrate stiffness, geometry as well as intercellular interactions affect collective cell behaviors and lead to complex tissue organization.