How do cells sense mechanical forces?

Title: Role of YAP/TAZ in mechanotransduction.

Authors: Sirio Dupont, Leonardo Morsut, Mariaceleste Aragona, Elena Enzo, Stefano Giulitti, Michelangelo Cordenonsi, Francesca Zanconato, Jimmy Le Digabel, Mattia Forcato, Silvio Bicciato, Nicola Elvassore, and Stefano Piccolo

Journal: Nature 474, 179-183 (2011)

In higher organisms, mechanical inputs along with chemical signals are crucial in guiding embryonic development and tissue remodeling, affecting for example stem cell differentiation.  As well as these downstream effects, we know many of the key molecular receptors – such as integrins, which allow cells to attach to the extracellular matrix and, when stretched, set off signaling cascades inside the cell.

But much less is understood about how the sensation of mechanical force at the cell surface is transduced into the cell nucleus and regulates the expression pattern of genes involved in cell decision processes.  Unlike with chemical signal transduction by receptor tyrosine kinases or GPCRs, the biochemical circuits that connect known mechanical sensors with the known, complex resulting phenotypes are largely unknown

Here, Dupont et al methodically uncovered one signal transduction pathway which mediates transcriptional regulation upon changes in matrix stiffness and cell shape.  They first computationally searched for common regulatory factors known to affect genes which are differentially in expressed in mammary epithilial cells grown or more or less stiff substrates.  They found that only gene regulation by YAP and TAZ correlated significantly with overexpression on high-stiffness substrates.  In the rest of the paper, the authors carefully tested which specific perturbations — including cell shape, tension, cytoskeletal polymerization, total adhesive cell-matrix contact area, etc — lead to YAP / TAZ activation (it’s shape and tension); and whether artificial depletion, or overexpression of an always-active YAP mutant, can mimic the effect of low and high substrate stiffness, respectively, on differentiation (yes).

Not only does this further our understanding of mechanobiology – it also suggests a way for cell engineers to detect and process mechanical signals in synthetic gene circuits.

Designing New Materials to Control Cell Development

Title: The influence of elasticity and surface roughness on myogenic and osteogenic-differentiation of cells on silk-elastin biomaterials

Authors: Xiao Hua, 1, Sang-Hyug Parka, 1, Eun Seok Gila, Xiao-Xia Xiaa, Anthony S. Weissb and David L. Kaplana

Journal: Biomaterials

Affiliation: a Department of Biomedical Engineering, Tufts University; b School of Molecular Bioscience, The University of Sydney

Being able to precisely control the differentiation of cells is an important tool for researchers wanting to make tissues of a specific function.  The differentiation of cells is dependent on the environment in which they are cultured.  In this paper the authors investigate tunable silk-tropoelastin biomaterials as a matrix to culture cells.  The researchers hope to correlate changes in the mechanical stiffness and surface morphology of these biomaterials to the response of C2C12 mouse myoblasts and human bone marrow stem cells (hMSCs).

In previous work, the researchers have shown they are able to form silk-tropoelastin biomaterials with a variety of properties by controlling the formation of the material and by further processing.  In this work they use different ratios of silk to tropoelastin and temperature controlled water vapor annealing to create biomaterials with a variety of surface morphologies and mechanical properties.  The authors used atomic force microscopy (AFM) to investigate the surface roughness.  Roughness increased with increased tropoelastin content.  Tensile stress-strain tests were performed to determine stiffness.  The authors found that increasing tropoelastin content decreased stiffness.

In agreement with previous studies, the researchers found that C2C12 cells proliferate and differentiate into myotubes more readily on a film with low roughness and high stiffness.  They determined that different micro/nano-porous patterns did not have a large effect on the proliferation and differentiation of the C2C12 cells.

In previous studies hMSCs have been shown to prefer rougher materials with rigidities lower than any of the rigidities studied in this paper.  hMSCs have been shown to have increased spreading with increased rigidity up to a certain point, but the rigidities of the materials discussed here had rigidities orders of magnitude higher.  The authors did find that the softest material tended to have cells with higher transcript levels and cell-matrix interactions which suggested to them that at this higher range of rigidities the lower stiffness may help proliferation and differentiation, the lower range might favor differentiation, or that other factors such as the biochemical nature of the material may be at play.

This paper is part of a large body of work exploring ways we can use mechanical cues to control cell differentiation.  This field will continue to be vitally important as we take biological engineering to the next level.