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Thursday, 05 April, 2018

Feeling the tension: Cells contract the matrix to modify its stiffness


Human breast cancer cells (blue) inside a collagen fiber matrix (green). The cells contract to strongly pull on the fiber matrix. Picture: C. Broedersz

Human breast cancer cells (blue) inside a collagen fiber matrix (green). The cells contract to strongly pull on the fiber matrix. Picture: C. Broedersz

Living cells inside a tissue can pull on their environment. NIM biophysicist Prof Chase Broedersz and colleagues demonstrated that this cellular pulling dramatically enhances the stiffness of the surrounding matrix. They developed a new method - the Nonlinear Stress Interference Microscopy (NSIM) - to measure elastic interactions between cells and the extracellular matrix.

Inside living organisms, cells naturally grow within the extracellular matrix, a 3D network of biopolymers. The mechanics of this matrix can strongly influence the behavior of living cells, an effect called mechanosensitivity. This mechanosensitivity can impact various cellular processes, including gene expression, cell migration and stem-cell differentiation.
Professor Opens external link in new windowChase Broedersz and colleagues at MIT, Paris and Princeton discovered that mechanical interactions between cells and the matrix go two ways: cells not only feel the stiffness of their surroundings, they also dramatically modify it. Cells adhere to the matrix and pull on, creating a tension in the surrounding matrix that increases its stiffness by a hundredfold. This is the first direct evidence that cells can use a mechanical contraction to modify the stiffness of their surrounding 3D tissue in such a dramatic way.

Nonlinear Stress Inference Microscopy (NSIM)
“When we walk across a bridge, this don’t affect the mechanical properties of this structure. Our study show that things are different for cells in tissues. As cells move through the matrix, they can pull on the structure to strongly enhance its stiffness”, explains Broedersz.
This increase of matrix stiffness is made possible because the stiffness of biopolymer matrices is highly nonlinear: the matrix stiffens when it deforms, unlike most regular non-biological materials. Broedersz and coworkers exploited this nonlinearity to develop a new method to characterize cell-matrix interactions. Their so-called Nonlinear Stress Inference Microscopy (NSIM) makes it possible to infer mechanical stresses induced by the cell in 3D. By measuring these stresses with NSIM, they could understand how cells interact mechanically with their surrounding extracellular matrix.
This study, published in Opens external link in new windowPNAS, highlights the importance of cellular stresses and matrix mechanics at the microscopic scale, and suggests a concrete mechanism through which cells can control their microenvironment and mechanically communicate with each other.

Cells actively enhance stiffness of the extracellular matrix
Using NSIM, Broedersz and colleagues could demonstrate that cell contraction induces large stresses, responsible for generating a massive stiffness gradient over an extended region in 3D matrices.
“Interestingly, in all matrix model systems we investigated experimentally, we found a universal behavior: cell-induced stresses propagate over unexpectedly large ranges.”, says Broedersz, “Put simply, stresses created by the cell propagate as in a network of ropes. This is different from expectations based on elastic theories for ordinary materials. These active stresses generated by the cell are capable of exciting the matrix’s nonlinear stiffening over large distances.”

Pulling beads away from contracting cells to “feel” the tension
In their experimental study, 3D biological matrices with embedded cells were infused with latex beads. The biophysicists used optical tweezers to pull on these beads. This allowed them to measure the tension and stiffness of the matrix at different locations around the cell.
“This enables us to directly measure how living cells mechanically modify their microenvironment.”, illustrates Broedersz. “The cell-induced stresses result in far-reaching stiffness changes. Other cells in the surrounding matrix could in principle sense and respond to these changes. This suggests that cell-induced matrix stiffening provides a concrete mechanism for mechanical communication between multiple cells in the matrix.”
These observations emphasize the critical role of nonlinear matrix mechanics in shaping cell-matrix interactions, and may regulate cell behaviors and physiological functionalities. Thanks to the simplicity of the NSIM method, it could be used in various contexts, including embryo and tumor development.

Cell contraction induces long-ranged stress stiffening in the extracellular matrix.
Han YL, Ronceray P, Xu G, Malandrino A, Kamm R, Lenz M, Broedersz CP, Guo M. PNAS April 4, 2018. 201722619; published ahead of print April 4, 2018. Opens external link in new windowdoi.org/10.1073/pnas.1722619115

Prof Dr Chase Broedersz
Theoretical Statistical and Biological Physics
Arnold Sommerfeld Center for Theoretical Physics
Ludwig Maximilians Universität
Theresienstraße 37
80333 Munich

Phone: +49 (0)89 2180 4514

E-Mail: Opens window for sending emailc.broedersz(at)lmu.de

Web: Opens external link in new windowwww.theorie.physik.uni-muenchen.de/lsfrey/group_broedersz/index.html


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