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Cell–extracellular matrix mechanotransduction in 3D

Nature Reviews Molecular Cell Biology volume 24, pages 495–516 (2023)Cite this article

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Abstract

Mechanical properties of extracellular matrices (ECMs) regulate essential cell behaviours, including differentiation, migration and proliferation, through mechanotransduction. Studies of cell–ECM mechanotransduction have largely focused on cells cultured in 2D, on top of elastic substrates with a range of stiffnesses. However, cells often interact with ECMs in vivo in a 3D context, and cell–ECM interactions and mechanisms of mechanotransduction in 3D can differ from those in 2D. The ECM exhibits various structural features as well as complex mechanical properties. In 3D, mechanical confinement by the surrounding ECM restricts changes in cell volume and cell shape but allows cells to generate force on the matrix by extending protrusions and regulating cell volume as well as through actomyosin-based contractility. Furthermore, cell–matrix interactions are dynamic owing to matrix remodelling. Accordingly, ECM stiffness, viscoelasticity and degradability often play a critical role in regulating cell behaviours in 3D. Mechanisms of 3D mechanotransduction include traditional integrin-mediated pathways that sense mechanical properties and more recently described mechanosensitive ion channel-mediated pathways that sense 3D confinement, with both converging on the nucleus for downstream control of transcription and phenotype. Mechanotransduction is involved in tissues from development to cancer and is being increasingly harnessed towards mechanotherapy. Here we discuss recent progress in our understanding of cell–ECM mechanotransduction in 3D.

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Fig. 1: Tissue mechanics, ECM components and cell–ECM mechanical interactions.
Fig. 2: Cell–matrix interactions in 3D.
Fig. 3: 2D and 3D mechanotransduction.
Fig. 4: Mechanotransduction in development.
Fig. 5: Mechanotransduction in tissues.

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Acknowledgements

The authors apologize for not being able to cite all the relevant publications in this Review due to space and reference limitations. O.C. acknowledges support from a National Institutes of Health National Cancer Institute grant (R37 CA214136), a National Science Foundation CAREER award (CMMI 1846367) and National Science Foundation grant MCB 2148041.

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  1. These authors contributed equally: Aashrith Saraswathibhatla, Dhiraj Indana.

Authors and Affiliations

  1. Department of Mechanical Engineering, Stanford University, Stanford, CA, USA

    Aashrith Saraswathibhatla, Dhiraj Indana & Ovijit Chaudhuri

  2. Sarafan ChEM-H, Stanford University, Stanford, CA, USA

    Ovijit Chaudhuri

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  1. Aashrith Saraswathibhatla
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Glossary

Advanced glycation end products

Proteins or lipids that are glycated when exposed to sugars, and are a biomarker implicated in many diseases, such as diabetes and atherosclerosis.

Aggrecan

The major proteoglycan in the articular cartilage which provides hydration to the cartilage.

Arginine–glycine–aspartate (RGD) sequences

A three-peptide cell–matrix adhesion motif derived from extracellular matrix proteins such as fibronectin and vitronectin that serves as a binding site for integrins such as αvβ3, α5β1 and αIIbβ3.

Assay for transposase-accessible chromatin using sequencing

(ATAC-seq). A genome wide assay that identifies accessible DNA regions/genome-wide chromatin accessibility.

Creep

A behaviour of viscoelastic materials, the time-dependent deformation or strain of a material under constant force/stress.

Deviatoric stresses

Distortional mechanical stresses that act to change the shape of an object on which they act, without changing its volume.

Fibrillar adhesions

Cell–extracellular matrix adhesions whose shapes are elliptical, often forming along fibrous extracellular matrix.

Filipodia

Actin-rich protrusions that are long and thin, and can be highly dynamic.

Fluorescence resonance energy transfer

Energy transfer between two light-sensitive molecules. The efficiency of this energy transfer is inversely proportional to the sixth power of the distance between the molecules. This can be used to study small changes in distances between molecules.

Focal adhesion kinase

(FAK). A receptor tyrosine kinase protein that localizes to focal complexes at cell–extracellular matrix adhesion sites and plays a crucial role in the several integrin-dependent mechanotransductive pathways.

Focal adhesions

Large cell–matrix adhesions typically formed by cells cultured on stiff 2D substrates, characterized by clustered integrin receptors, localization of proteins such as paxillin, talin, vinculin, and phosphorylated focal adhesion kinase (FAK) and thick actomyosin stress fibres, mediating strong cell–substrate adhesion.

Hydrostatic stresses

Volumetric or dilational stresses that act to increase or decrease the volume of an object on which they act, without changing its shape.

Invadopodia

Actin-rich structures that are present at the basal surface of cells, and that are thought to degrade and apply forces to extracellular matrix.

Lamellipodia

Thin sheet-like protrusions composed of a branched network of actin filaments. Extension of lamellipodia at the leading edge is often implicated in driving cell migration.

Lysyl oxidase

An enzyme that converts lysine molecules into highly reactive aldehydes that form crosslinks in extracellular matrix proteins such as type I collagen and elastin.

Matrix metalloproteinases

Cell-secreted enzymes that are capable of proteolytically degrading various extracellular matrix components.

Mechanical plasticity

A material property that defines the extent to which the material undergoes permanent or irreversible deformation following the application and release of external deformation or loading.

Mechanosensitive ion channels

Ion channels that open or close in response to cell membrane stretch or tension. TRPV4 and PIEZO1 are examples of mechanosensitive ion channels implicated in mechanotransduction.

Mesenchymal stem cells

(MSCs). Multipotent stem cells that are found in the bone marrow, which have been reported to differentiate into osteoblasts, adipocytes, chondrocytes, myocytes and neurons.

Microtentacles

Microtubule-based membrane protrusions which are often observed in detached circulating tumour cells.

MRTF-A

Myocardin-related transcription factor A, a transcription factor that plays a key role in mediating smooth muscle cell differentiation.

Nonlinear elasticity

Elasticity is the ability of a material to retain its initial shape/configuration following the application and release of external deformation or loading. Nonlinear elasticity is defined as the nonlinear relation between stress and strain for a material, in contrast to linear elasticity, which is defined as the linear relation between stress and strain of a material until the material starts to yield.

Poroelasticity

A material property that describes the interaction between fluid flow and solid deformations within a porous material. Cells and extracellular matrices are usually poroelastic.

Proteoglycans

Supramolecules that posses protein as a core and a side chain of sugars.

Reconstituted BM (rBM) matrices

Commercially available matrices such as Matrigel or Geltrex that are derived from Engelbreth–Holm–Swarm tumour, a mouse sarcoma, and that are commonly used for in vitro cell culture and contain laminin, type IV collagen, entactin, perlecan and other components.

RHAMM

Receptor for hyaluronan-mediated motility, a protein which binds to hyaluronan.

Rho signalling

A cell signalling pathway involved in regulation of a wide variety of cell processes, such as cell spreading, survival, proliferation and adhesion.

Stiffness

The resistance to deformation of a specific structure, which is dependent on the Young’s modulus and geometry of the structure. Hence, stiffness is regarded as a property of a specific structure, whereas Young’s modulus is an inherent property of the material.

Strain

A measure of localized deformation in a material, with uniaxial strain typically defined as the ratio of deformation to the original length of the material.

Stress

A measure of force per unit area, which has the unit of pascals.

Stress relaxation

A behaviour of viscoelastic materials referring to the time-dependent change in stress in a material under constant deformation.

Tenascin C

A multimodular extracellular matrix glycoprotein which is expressed in various tissues during development, disease or injury.

Traction force microscopy

A technique that experimentally measures the force-induced displacement field of a substrate with known mechanical properties and uses this to computationally determine the cell–extracellular matrix forces applied to the substrate.

Versican

A large extracellular matrix proteoglycan that is found in various tissues, such as blood vessels and skin.

Viscoelasticity

A property of materials that exhibit some behaviours characteristic of elastic solids and some of viscous liquids, and is characterized by a time-dependent mechanical response (that is, creep or stress relaxation).

YAP and TAZ

Transcription co-activators that shuttle between the nucleus and the cytoplasm and play an important role in mediating mechanotransduction, particularly in 2D. When translocated to the nucleus, YAP and TAZ do not directly bind to DNA but regulate gene expression through their binding to transcription factors of the TEAD family.

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Saraswathibhatla, A., Indana, D. & Chaudhuri, O. Cell–extracellular matrix mechanotransduction in 3D. Nat Rev Mol Cell Biol 24, 495–516 (2023). https://doi.org/10.1038/s41580-023-00583-1

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