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    Mechanobiology at Institut Cochin


    1 - Mechanobiology

    What is it?

    Mechanobiology, the science of the mechanics (forces and physical interactions) of biological systems, studies the functional relationships between the physical constants of a tissue and its biological responses. Cells adapt their overall metabolism and behaviour to their environment and in turn act on it. They are able to detect the properties of their mechanical environment (mechano-detection) and to respond to them (mechano-transduction).

    Thus, changes in shape, polarity and migration associated or not with changes in the fate and identity of the cell are the consequence of the response to mechanical information (shear forces, viscoelasticity of the substrate, osmotic pressure, rigidity, stretching, gravity, etc.). Tissues have a wide range of degrees of stiffness (Figure 1) (Engler, Cell 2006 126 677-89). Mechanical signals are "translated" into biochemical signals (e. g. phosphorylations, modification of protein folding) and interpreted by the cell for dynamic reorganization of the cytoskeleton, sub-cellular relocation of regulatory proteins and gene expression.

    Figure 1:
    (A) Extent of rigidity of solid tissues defined by their modulus of elasticity, E. (Barnes JM, Journal of Cell Science 2017 130: 71-82).
    (B) Differential spreading of stem cells (MSC) after seeding on collagen-I-coated gels whose E value mimics that of the brain (0.1 to 1 kPa), muscle (8-17 kPa) or more rigid (25-40 kPa) respectively, from left to right. Bars: 20 µm. (Engler, Cell 2006 126 677-89).


    Relationship to physiology? pathophysiology?

    Measuring forces and understanding their impact on cellular physiology is the basis for analyzing tissue architecture and dynamics in normal and pathological situations. Tissue mechanics are altered in various types of pathological situations: in certain cancers where an increase in rigidity is associated with a higher metastatic potential, during inflammation, during the rigidification of coronary arteries, following a violent shock with ossification of muscle tissues (osteoma) etc... On the other hand, forced immobilization or weightlessness leads to a loss of rigidity (osteoporosis).

    The facility "BioMecan'IC" is continuing and finalizing its construction phase and is being structured. Here we will present some biomechanical questions that BioMecan'IC strives to answer (see the platform page on the Institute website for more details).


    2 - The questions we ask and the techniques that answer them

    A - How do cells/tissues respond to the environment (in terms of 2-dimensional rigidity)?

    Homogeneous environment

    Gels of variable stiffness homogeneously functionalized by adhesion molecules mimic the cellular micro-environment. These surfaces constitute a culture substrate for cells and make it possible to monitor their behaviour, measure various parameters (spreading, migration, etc.) and study the sub-cellular location of markers of interest. Polyacrylamide gels and an elastomer, PDMS (polydimethylsiloxane), are preferred (Figure 2). The rigidity of the gel can be modified by varying the ratio of its component reagents (acrylamide/bis-acrylamide). Abacuses exist to establish the protocol and a control measurement can be made for example by AFM (Atomic Force Microscopy) in collaboration with Jean-Marc DiMeglio (MSC Saints-Pères).

    Figure 2: Diagram describing the manufacture of polyacrylamide gels.


    Constrained environment in terms of form and area

    Microprinting is used to design and "draw" shapes that will constrain the adhesion of cells on surfaces of various areas and shapes (lines, broken lines, discs, "letters X, N, H, I, etc"). This technique allows to study the cellular migration and the more or less coordinated displacement of cellular organelles, the implementation of focal adhesions, cytoskeleton, etc.

    These issues can be addressed by coupling differential functionality with various rigidities of polyacrylamide gels (Figure 3).

    Figure 3: (A) Diagram describing microprinting from an "ink pad", (B) cells spread on a square surface printed on a polyacrylamide gel (94 kPa). Source: "BioMecan'IC"


    Measurement of the forces that the cells develop (TFM)

    Cells exert tensile forces on their environment that allow them to migrate and maintain tissue integrity. The Traction Force Microscopy (TFM) technique allows the measurement of the tensile forces developed by the cells on an elastic substrate and thus provides quantitative information on cellular mechanics (Figure 4). TFM uses polyacrylamide gels in which small fluorescent beads (170 nm) are incorporated. These gels being elastic, the cells will "crumple" them, slightly moving the beads. By comparing the positions of the beads at rest and in the presence of cells, their displacement is deduced and the intensity of the forces involved is calculated using an appropriate algorithm.

    Figure 4: (A) Principle of the TFM. (Suné-Aunon A BioInformatics 2017 18 365) (B) Measurement of the forces developed by a fibroblast. Source: BioMecan'IC.


    B - Study of the deformability of membranes and cellular organelles (microsuction/micropipette aspiration MPA)

    Cells have membrane and organelle properties that vary according to cell type, their progress in the differentiation process or during mutations (lamins A/C: J Cell Physiol. 2018 233: 5112-8). By the MPA technique, membrane stiffness can be evaluated. For this purpose, micropipettes with an inner diameter smaller than the cell diameter are used. When a depression is applied to the cell surface, a fraction of the cell is sucked into the capillary and deformed (Figure 5). The geometry of the aspirated fraction as well as the applied depression allow the measurement of cellular deformability. The red blood cell membrane has been extensively studied, however the scope of this technique is vast and also allows to study the response of cells to the stress imposed by suction by following for example the relocation of fluorescent markers.

    Figure 5: Schematic diagram of the principle. The deformability of the membrane is measured by taking into account the length of the membrane sucked into the pipette and the vacuum applied.


    This presentation reflects the approaches implemented by BioMecan'IC and those that are in the planning stages in the short term. Of course, BioMecan'IC cannot offer all the services that can be considered by teams. However, BioMecan'IC can advise, provide expertise and direct towards its scientific and technical relations.



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