Extracellular matrix viscoelasticity and cellular mechanotransduction

Mechanotransduction refers to the process by which cells sense and respond to mechanical cues. It has been found that cells sense and respond to extracellular matrix (ECM) elasticity. However, reconstituted ECM and soft tissues are often viscoelastic, exhibiting stress relaxation and creep, and can exhibit mechanically plasticity. We have found that extracellular matrix viscoelasticity and plasticity regulate various cellular behaviors, such as spreading, differentiation, matrix formation, matrix remodeling, migration, and division. We seek to determine the viscoelasticity and plasticity of physiologically relevant extracellular matrices and the mechanisms underlying these mechanical behaviors, elucidate the mechanisms by which matrix viscoelasticity and plasticity influences cell biology, and harness these insights towards the development of new therapies and regenerative medicine.

Relevant publications: 1. Lee, et al, Mechanical confinement regulates cartilage matrix formation by chondrocytes , Nature Materials (2017). 2. Lou, et al., Stress Relaxing Hyaluronic Acid-Collagen Hydrogels Promote Cell Spreading, Fiber Remodeling, and Focal Adhesion Formation in 3D Cell Culture, Biomaterials, 2018. 3. Nam, et al., Viscoplasticity Enables Mechanical Remodeling of Matrix by Cells, Biophysical Journal (2016). 4. Nam, et al., Strain-enhanced stress relaxation impacts nonlinear elasticity in collagen gels, PNAS (2016). 5. Chaudhuri, et al., Hydrogels with tunable stress relaxation regulate stem cell fate and activity, Nature Materials (2016). 6. Chaudhuri, et al., Substrate stress relaxation regulates cell spreading, Nature Communications (2015).

Biophysics of cell migration

Cell migration is critical for development, immune cell trafficking, wound healing, and metastasis. In many contexts, cells migrate through three-dimensionally confining microenvironments, where extracellular matrix pore size is smaller than that of the cells. For example, during cancer progression, carcinoma cells on the order of 10 microns in size must invade through a nanoporous basement membrane as a first step towards metastasis. We are investigating how cells push, pull, and degrade matrix in order to migrate through 3D tissue microenvironments. A particular area of interest is in understanding the role of matrix mechanical plasticity in mediating invasion and migration of cancer cells.

Relevant publications: Wisdom, et al, Matrix mechanical plasticity regulates cancer cell migration through confining microenvironments , Nature Communications (2018).

Cell division: force generation and mechanotransduction

In many physiological contexts, cells divide in mechanically confining viscoelastic microenvironments, where they are surrounded by neighboring cells and ECM. Most of what is known about cell division is based on studies of cells dividing on 2D substrates, where they can simply release from the substrate and divide unrestricted. A mechanically confining microenvironment would be expected to restrict various morphological processes associated with cell cycle progression and cell division. We aim to uncover the how confinement impacts cell cycle progression, and how cells generate forces in order to divide in confining microenvironments.

Relevant publications: Nam and Chaudhuri, Mitotic cells generate protrusive extracellular forces to divide in three-dimensional microenvironments , Nature Physics (2018).

Mechanics of breast cancer progression

Increased mammographic density, associated with an increase in tissue stiffness, is one of the strongest and most consistent risk factors for breast cancer progression. Various studies have established that increased stiffness promotes cancer progression, but the mechanisms mediating the effect of stiffness remain unclear. We seek to understand the mechanisms underlying the impact of increased stiffness on breast cancer progression in terms of cell-matrix interactions, and transcriptional and epigenetic regulation. Our vision is that by better understanding how mechanics influences breast cancer progression, we can develop more effective diagnostics and therapies.

Relevant publications: 1. Chaudhuri, et al. Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium, Nature Materials (2014). 2. Lee and Chaudhuri,Regulation of breast cancer progression by extracellular matrix mechanics: insights from 3D culture models, ACS Biomat. Sci. and Eng. (2017).

Biopolymer gel mechanics and biomaterials development

Many biological materials, from the actin cytoskeleton inside cells, which governs their shape and rigidity, to the extracellular matrix, consist of semiflexible biopolymer networks. These networks are typically organized in specific architectures, and are often under tensional or compressional forces. These networks often have unique behaviors of nonlinear elasticity, viscoelasticity, plasticity, and toughness but the molecular mechanisms underlying these behaviors are not fully understood. Our goal is to elucidate the molecular mechanisms that govern the mechanics of these networks, and to use this understanding to engineer biomaterials with useful mechanical properties for use in tissue engineering and other applications.

Relevant publications: 1. Nam, et al., Strain-enhanced stress relaxation impacts nonlinear elasticity in collagen gels, PNAS (2016). 2. Nam, et al., Viscoplasticity Enables Mechanical Remodeling of Matrix by Cells, Biophysical Journal (2016). 3. Lam, Chaudhuri, et al., Mechanics and contraction dynamics of single platelets and implications for clot stiffening, Nature Materials (2011). 4. Chaudhuri, et al., Reversible stress softening of actin networks, Nature (2007).

New tools for force microscopy

Forces and mechanics at the micro and nanoscale play a key role in regulating cell-matrix interactions, but current approaches to measure these have limitations. Thus, there is a critical need for new tools to probe forces and mechanics at the micro and nanoscales. We are developing tools that provide new capabilities in this space.

Relevant publications: Chaudhuri, et al., Combined atomic force microscopy and side-view optical imaging for mechanical studies of cells , Nature Methods(2009).