Cyclic stretching of soft substrates induces spreading and growth

Cui, Yukun; Hameed, Feroz M.; Yang, Bo; Lee, Kyung‐Hee; Pan, Catherine; Park, Sungsu; Sheetz, Michael P.

doi:10.1038/ncomms7333

Cited by 260 publications

(236 citation statements)

References 33 publications

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“…TAZ modulates the balance of differentiation between adipocytes and osteoblasts in MSCs (Hong et al, 2005). In addition, physical cues, including cell morphology and ECM stiffness, controls YAP/TAZ subcellular localization and function (Aragona et al, 2013;Cui et al, 2015;Dupont et al, 2011;Wada et al, 2011). YAP/TAZ is preferentially accumulated within the nucleus and becomes transcriptionally active on rigid ECM to promote osteogenesis, whereas it accumulates within the cytosol on soft ECM (Hwang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Vinculin promotes nuclear localization of TAZ to inhibit ECM stiffness-dependent differentiation into adipocytes

Kuroda

Wada

Kimura

et al. 2017

Journal of Cell Science

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Extracellular matrix (ECM) stiffness regulates the lineage commitment of mesenchymal stem cells (MSCs). Although cells sense ECM stiffness through focal adhesions, how cells sense ECM stiffness and regulate ECM stiffness-dependent differentiation remains largely unclear. In this study, we show that the cytoskeletal focal adhesion protein vinculin plays a critical role in the ECM stiffness-dependent adipocyte differentiation of MSCs. ST2 mouse MSCs differentiate into adipocytes and osteoblasts in an ECM stiffness-dependent manner. We find that a rigid ECM increases the amount of cytoskeleton-associated vinculin and promotes the nuclear localization and activity of the transcriptional coactivator paralogs Yes-associated protein (YAP, also known as YAP1) and transcriptional coactivator with a PDZ-binding motif (TAZ, also known as WWTR1) (hereafter YAP/TAZ). Vinculin is necessary for enhanced nuclear localization and activity of YAP/TAZ on the rigid ECM but it does not affect the phosphorylation of the YAP/TAZ kinase LATS1. Furthermore, vinculin depletion promotes differentiation into adipocytes on rigid ECM, while it inhibits differentiation into osteoblasts. Finally, TAZ knockdown was less effective at promoting adipocyte differentiation in vinculin-depleted cells than in control cells. These results suggest that vinculin promotes the nuclear localization of transcription factor TAZ to inhibit the adipocyte differentiation on rigid ECM.

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Section: Introductionmentioning

confidence: 99%

Vinculin promotes nuclear localization of TAZ to inhibit ECM stiffness-dependent differentiation into adipocytes

Kuroda

Wada

Kimura

et al. 2017

Journal of Cell Science

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“…[1][2][3][4] Cells sense and respond to mechanical cues, such as the mechanical strains and the rigidity of their extracellular matrix (ECM), by adjusting the transmembrane molecules (e.g., integrins) and by reorganizing the intracellular cytoskeleton. 5,6 Tools for studying strain responses of cells in two-dimensional (2D) environment, including stretchable substrata, 7 micropost arrays 8 and 2D traction microscopy, 9 are well established. However, observations from these tools are difficult to extend to three-dimensional (3D) culture environments because of fundamental differences in the morphologies and functionalities of cells in 2D and 3D cultures.…”

Section: Introductionmentioning

confidence: 99%

Magnetically actuated cell-laden microscale hydrogels for probing strain-induced cell responses in three dimensions

Huang

Gao

et al. 2016

NPG Asia Mater

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Living cells respond to their mechanical microenvironments during development, healing, tissue remodeling and homeostasis attainment. However, this mechanosensitivity has not yet been established definitively for cells in three-dimensional (3D) culture environments, in part because of challenges associated with providing uniform and consistent 3D environments that can deliver a large range of physiological and pathophysiological strains to cells. Here, we report microscale magnetically actuated, cell-laden hydrogels (μMACs) for investigating the strain-induced cell response in 3D cultures. μMACs provide high-throughput arrays of defined 3D cellular microenvironments that undergo reversible, relatively homogeneous deformation following non-contact actuation under external magnetic fields. We present a technique that not only enables the application of these high strains (60%) to cells but also enables simplified microscopy of these specimens under tension. We apply the technique to reveal cellular strain-threshold and saturation behaviors that are substantially different from their 2D analogs, including spreading, proliferation, and differentiation. μMACs offer insights for mechanotransduction and may also provide a view of how cells respond to the extracellular matrix in a 3D manner.

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“…The magneto-active substrates developed here complement the current cell stretching technologies used to establish that cells change contractility, spreading phenotype, fibre formation and proliferation differently for different mechanical stimulation patterns 8,[17][18][19] . Indeed, the present work demonstrates that magneto-active substrates made of soft magnetic micro-pillars embedded in a soft elastomer uniquely combine advantages that were not associated so far.…”

Section: Discussionmentioning

confidence: 99%

“…In their natural environment, cells face a complex and dynamic mechanical environment. Cyclic strain can induce reorientation of adherent cells and affect cell growth depending on the temporal and spatial properties of the mechanical stimulation [8][9][10][11] . The relevant timescales span from the milli-second for the stretching of mechanosensitive proteins, minutes for mechanotransduction signalling to hours for global morphological changes and even longer for adapting cell functions 12 .…”

mentioning

confidence: 99%

“…Although local enough to address the subcellular mechanisms of mechanotransduction, these methods involve intrinsic perturbations of the cell structure through mechanical interactions with a stiff object of fixed geometry. Cell stretchers were developed to induce mechanical stimulation via substrates of tunable substrate rigidity 8,17 . Despite being more physiological and less invasive, such approaches only enable global deformation at the cellular scale.…”

mentioning

confidence: 99%

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Magneto-Active Substrates for Local Mechanical Stimulation of Living Cells

Coullomb

Bidan

Fratzl

et al. 2018

Biophysical Journal

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Cells are able to sense and react to their physical environment by translating a mechanical cue into an intracellular biochemical signal that triggers biological and mechanical responses. This process, called mechanotransduction, controls essential cellular functions such as proliferation and migration. The cellular response to an external mechanical stimulation has been investigated with various static and dynamic systems, so far limited to global deformations or to local stimulation through discrete substrates. To apply local and dynamic mechanical constraints at the single cell scale through a continuous surface, we have developed and modelled magneto-active substrates made of magnetic micro-pillars embedded in an elastomer. Constrained and unconstrained substrates are analysed to map surface stress resulting from the magnetic actuation of the micro-pillars and the adherent cells. These substrates have a rigidity in the range of cell matrices, and the magnetic micro-pillars generate local forces in the range of cellular forces, both in traction and compression. As an application, we followed the protrusive activity of cells subjected to dynamic stimulations. Our magneto-active substrates thus represent a new tool to study mechanotransduction in single cells, and complement existing techniques by exerting a local and dynamic stimulation, traction and compression, through a continuous soft substrate.Living cells have a sense of touch, which means that they are able to feel, respond and adapt to the mechanical properties of their environment. The process by which cells convert mechanical signals into biochemical signals is called mechanotransduction. Defects in the mechanotransduction pathways are implicated in numerous diseases ranging from atherosclerosis and osteoporosis to cancer progression and developmental disorders 1,2 . Since the 1990s, different static studies focused on mechanosensing have shown that cells can migrate along the rigidity gradient direction 3 and that stem cells can differentiate in vitro according to their substrate's stiffness 4 and geometry 5 . The interplay between a mechanical force and the reinforcement of cell adhesion has also been documented 6,7 . In their natural environment, cells face a complex and dynamic mechanical environment. Cyclic strain can induce reorientation of adherent cells and affect cell growth depending on the temporal and spatial properties of the mechanical stimulation [8][9][10][11] . The relevant timescales span from the milli-second for the stretching of mechanosensitive proteins, minutes for mechanotransduction signalling to hours for global morphological changes and even longer for adapting cell functions 12 . Taken together, previous works have shown that cells are sensitive to both the spatial and temporal signatures of mechanical stimuli. In order to study mechanotransduction, it is thus essential to stimulate cells with mechanical cues controlled both spatially and temporally.To address this topic, various methods have been proposed to exert experim...

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Cyclic stretching of soft substrates induces spreading and growth

Cited by 260 publications

References 33 publications

Vinculin promotes nuclear localization of TAZ to inhibit ECM stiffness-dependent differentiation into adipocytes

Vinculin promotes nuclear localization of TAZ to inhibit ECM stiffness-dependent differentiation into adipocytes

Magnetically actuated cell-laden microscale hydrogels for probing strain-induced cell responses in three dimensions

Magneto-Active Substrates for Local Mechanical Stimulation of Living Cells

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