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Cell-extracellular matrix mechanotransduction in 3D.

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.

SUBMITTER: Saraswathibhatla A

PROVIDER: S-EPMC10656994 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Cell-extracellular matrix mechanotransduction in 3D.

Saraswathibhatla Aashrith A Indana Dhiraj D Chaudhuri Ovijit O

Nature reviews. Molecular cell biology 20230227 7

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 ...[more]

PMID: 36849594

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Project description:Extracellular matrix (ECM) is comprised of different types of proteins, which change in composition and ratios during morphogenesis and disease progression. ECM proteins provide cell adhesion and impart mechanical cues to the cells. Increasing substrate stiffness has been shown to induce Yes-associated protein (YAP) translocation from the cytoplasm to the nucleus, yet these mechanistic studies used fibronectin only as the biochemical cue. How varying the types of ECM modulates mechanotransduction of stem cells remains largely unknown. Using polyacrylamide hydrogels with tunable stiffness as substrates, here we conjugated four major ECM proteins commonly used for cell adhesion: fibronectin, collagen I, collagen IV and laminin, and assessed the effects of varying ECM type and density on YAP translocation in human mesenchymal stem cells (hMSCs). For all four ECM types, increasing ECM ligand density alone can induce YAP nuclear translocation without changing substrate stiffness. The ligand threshold for such biochemical ligand-induced YAP translocation differs across ECM types. While stiffness-dependent YAP translocation can be induced by all four ECM types, each ECM requires a different optimized ligand density for this to occur. Using antibody blocking, we further identified integrin subunits specifically involved in mechanotransduction of different ECM types. Finally, we demonstrated that altering ECM type further modulates hMSC osteogenesis without changing substrate stiffness. These findings highlight the important role of ECM type in modulating mechanotransduction and differentiation of stem cells, and call for future mechanistic studies to further elucidate the role of changes in ECM compositions in mediating mechanotransduction during morphogenesis and disease progression. STATEMENT OF SIGNIFICANCE: Our study addresses a critical gap of knowledge in mechanobiology. Increasing substrate stiffness has been shown to induce nuclear YAP translocation, yet only on fibronectin-coated substrates. However, extracellular matrix (ECM) is comprised of different protein types. How varying the type of ECM modulates stem cell mechanotransduction remains largely unknown. We here reveal that the choice of ECM type can directly modulate stem cell mechanotransduction, filling this critical gap. This work has broad impacts in mechanobiology and biomaterials, as it provides the first evidence that varying ECM type can impact YAP translocation independent of substrate stiffness, opening doors for a more rational biomaterials design tuning ECM properties to control cell fate for promoting normal development and for preventing disease progression.

Dataset Information

Cell-extracellular matrix mechanotransduction in 3D.

Publications

Cell-extracellular matrix mechanotransduction in 3D.

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