Cytoskeletal Tension

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Christopher S Chen - One of the best experts on this subject based on the ideXlab platform.

  • activation of beta 1 but not beta 3 integrin increases cell traction forces
    FEBS Letters, 2013
    Co-Authors: Grace L Lin, Daniel M Cohen, Ravi A Desai, Mark T Breckenridge, Lin Gao, Martin J Humphries, Christopher S Chen
    Abstract:

    Cell-generated traction forces induce integrin activation, leading to focal adhesion growth and cell spreading. It remains unknown, however, whether integrin activation feeds back to impact the generation of Cytoskeletal Tension. Here, we used elastomeric micropost arrays to measure cellular traction forces in wildtype and integrin-null cells. We report that activation of β1 but not β3 integrin, by either increasing density of immobilized fibronectin or treating with manganese, elicited fibroblast spreading and Cytoskeletal Tension. Furthermore, this force generation required Rho kinase and myosin activity. These findings suggest that integrin activation and cell traction forces comprise a bi-directional signaling unit of cell adhesion.

  • bone morphogenetic protein 2 induced signaling and osteogenesis is regulated by cell shape rhoa rock and Cytoskeletal Tension
    Stem Cells and Development, 2012
    Co-Authors: Yang Kao Wang, Michael T Yang, Daniel M Cohen, Michele A Wozniak, Lingjie Gao, Jeroen Eyckmans, Christopher S Chen
    Abstract:

    Osteogenic differentiation of human mesenchymal stem cells (hMSCs) is classically thought to be mediated by different cytokines such as the bone morphogenetic proteins (BMPs). Here, we report that cell adhesion to extracellular matrix (ECM), and its effects on cell shape and Cytoskeletal mechanics, regulates BMP-induced signaling and osteogenic differentiation of hMSCs. Using micropatterned substrates to progressively restrict cell spreading and flattening against ECM, we demonstrated that BMP-induced osteogenesis is progressively antagonized with decreased cell spreading. BMP triggered rapid and sustained RhoA/Rho-associated protein kinase (ROCK) activity and contractile Tension only in spread cells, and this signaling was required for BMP-induced osteogenesis. Exploring the molecular basis for this effect, we found that restricting cell spreading, reducing ROCK signaling, or inhibiting Cytoskeletal Tension prevented BMP-induced SMA/mothers against decapentaplegic (SMAD)1 c-terminal phosphorylation, SMAD1 dimerization with SMAD4, and SMAD1 translocation into the nucleus. Together, these findings demonstrate the direct involvement of cell spreading and RhoA/ROCK-mediated Cytoskeletal Tension generation in BMP-induced signaling and early stages of in vitro osteogenesis, and highlight the essential interplay between biochemical and mechanical cues in stem cell differentiation.

  • emergence of patterned stem cell differentiation within multicellular structures
    Stem Cells, 2008
    Co-Authors: Sami Alom Ruiz, Christopher S Chen
    Abstract:

    The ability of stem cells to differentiate into specified lineages in the appropriate locations is vital to morphogenesis and adult tissue regeneration. Although soluble signals are important regulators of patterned differentiation, here we show that gradients of mechanical forces can also drive patterning of lineages. In the presence of soluble factors permitting osteogenic and adipogenic differentiation, human mesenchymal stem cells at the edge of multicellular islands differentiate into the osteogenic lineage, whereas those in the center became adipocytes. Interestingly, changing the shape of the multicellular sheet modulated the locations of osteogenic versus adipogenic differentiation. Measuring traction forces revealed gradients of stress that preceded and mirrored the patterns of differentiation, where regions of high stress resulted in osteogenesis, whereas stem cells in regions of low stress differentiated to adipocytes. Inhibiting Cytoskeletal Tension suppressed the relative degree of osteogenesis versus adipogenesis, and this spatial patterning of differentiation was also present in three-dimensional multicellular clusters. These findings demonstrate a role for mechanical forces in linking multicellular organization to spatial differentials of cell differentiation, and they represent an important guiding principle in tissue patterning that could be exploited in stem cell-based therapies. Disclosure of potential conflicts of interest is found at the end of this article.

  • activation of rock by rhoa is regulated by cell adhesion shape and Cytoskeletal Tension
    Experimental Cell Research, 2007
    Co-Authors: Kiran Bhadriraju, Dana M Pirone, John L Tan, Michael T Yang, Sami Alom Ruiz, Christopher S Chen
    Abstract:

    Adhesion to the extracellular matrix regulates numerous changes in the actin cytoskeleton by regulating the activity of the Rho family of small GTPases. Here, we report that adhesion and the associated changes in cell shape and Cytoskeletal Tension are all required for GTP-bound RhoA to activate its downstream effector, ROCK. Using an in vitro kinase assay for endogenous ROCK, we found that cells in suspension, attached on substrates coated with low density fibronectin, or on spreading-restrictive micropatterned islands all exhibited low ROCK activity and correspondingly low myosin light chain phosphorylation, in the face of high levels of GTP-bound RhoA. In contrast, allowing cells to spread against substrates rescued ROCK and myosin activity. Interestingly, inhibition of Tension with cytochalasin D or blebbistatin also inhibited ROCK activity within 20 min. The abrogation of ROCK activity by cell detachment or inhibition of Tension could not be rescued by constitutively active RhoA-V14. These results suggest the existence of a feedback loop between Cytoskeletal Tension, adhesion maturation, and ROCK signaling that likely contributes to numerous mechanochemical processes.

  • an inhibitory role for fak in regulating proliferation a link between limited adhesion and rhoa rock signaling
    Journal of Cell Biology, 2006
    Co-Authors: Dana M Pirone, Sami Alom Ruiz, Lin Gao, Wendy F Liu, Srivatsan Raghavan, Christopher A Lemmon, Lewis H Romer, Christopher S Chen
    Abstract:

    Focal adhesion kinase (FAK) transduces cell adhesion to the extracellular matrix into proliferative signals. We show that FAK overexpression induced proliferation in endothelial cells, which are normally growth arrested by limited adhesion. Interestingly, displacement of FAK from adhesions by using a FAK−/− cell line or by expressing the C-terminal fragment FRNK also caused an escape of adhesion-regulated growth arrest, suggesting dual positive and negative roles for FAK in growth regulation. Expressing kinase-dead FAK-Y397F in FAK−/− cells prevented uncontrolled growth, demonstrating the antiproliferative function of inactive FAK. Unlike FAK overexpression–induced growth, loss of growth control in FAK−/− or FRNK-expressing cells increased RhoA activity, Cytoskeletal Tension, and focal adhesion formation. ROCK inhibition rescued adhesion-dependent growth control in these cells, and expression of constitutively active RhoA or ROCK dysregulated growth. These findings demonstrate the ability of FAK to suppress and promote growth, and underscore the importance of multiple mechanisms, even from one molecule, to control cell proliferation.

Donald E Ingber - One of the best experts on this subject based on the ideXlab platform.

  • deformability in adherent endothelial cells is Cytoskeletal Tension a major determinant of cell
    2013
    Co-Authors: Jeffrey J. Fredberg, Jacob Pourati, Jonathan L Schaffer, Dimitrije Stamenovic, Andrew Maniotis, Donald E Ingber, Ning Wang, David Spiegel, James P Butler
    Abstract:

    You might find this additional info useful...This article cites€30 articles, 14 of which you can access for free at: http://ajpcell.physiology.org/content/274/5/C1283.full#ref-list-1This article has been cited by€20 other HighWire-hosted articles: http://ajpcell.physiology.org/content/274/5/C1283#cited-by Updated information and services including high resolution figures, can be found at: http://ajpcell.physiology.org/content/274/5/C1283.fullfound at: Additional material and information about American Journal of Physiology - Cell Physiology can behttp://www.the-aps.org/publications/ajpcellThis information is current as of February 22, 2013.

  • l caldesmon regulates proliferation and migration of vascular smooth muscle cells and inhibits neointimal formation after angioplasty
    Arteriosclerosis Thrombosis and Vascular Biology, 2006
    Co-Authors: Kazuhiko Yokouchi, Yasushi Numaguchi, Ryuji Kubota, Masakazu Ishii, Hajime Imai, Ryuichiro Murakami, Yasuhiro Ogawa, Takahisa Kondo, Kenji Okumura, Donald E Ingber
    Abstract:

    Objective— Light-type caldesmon ( l -CaD) is a potent cytostatic and antiangiogenic protein that regulates cell growth and survival via modulation of the cell shape and cytoskeleton. The aim of this study is to explore the potential value of l -CaD for use as a cytostatic agent to inhibit neointimal formation after angioplasty by suppressing vascular smooth muscle cell (VSMC) growth and migration. Methods and Results— We tested the cytostatic function of l -CaD in cultured VSMCs using assays for apoptosis, cell proliferation, and migration, and evaluated the expression pattern of relevant signaling proteins (focal adhesion kinase [FAK] and mitogen-activated protein kinases) in VSMCs. Transfection of adenoviral vector encoding l -CaD (Ad- l -CaD) resulted in progressive loss of actin stress fibers and cell retraction. Enzyme-linked immunosorbent assay demonstrated that Ad- l -CaD transfection increased the apoptosis rate by 75% and reduced BrdU uptake by 49%. Furthermore, transfection of Ad- l -CaD inhibited migration of VSMCs induced by platelet-derived growth factor-BB (PDGF) by 36% ( P l -CaD overexpression reduced PDGF-induced phosphorylation of both FAK and extracellular signal regulated-kinase (ERK). In balloon-injured rat carotid arteries, Ad- l -CaD transfection inhibited neointimal formation by 37% ( P Conclusions— Overexpression of l -CaD suppressed cell growth and survival in VSMCs and inhibited neointimal formation after experimental angioplasty, partly by regulating the Cytoskeletal Tension-FAK-ERK axis.

  • mechanical forces alter zyxin unbinding kinetics within focal adhesions of living cells
    Journal of Cellular Physiology, 2006
    Co-Authors: Tanmay P Lele, Jay Pendse, Sanjay Kumar, Matthew C Salanga, John Karavitis, Donald E Ingber
    Abstract:

    The formation of focal adhesions that mediate alterations of cell shape and movement is controlled by a mechanochemical mechanism in which Cytoskeletal Tensional forces drive changes in molecular assembly; however, little is known about the molecular biophysical basis of this response. Here, we describe a method to measure the unbinding rate constant k(OFF) of individual GFP-labeled focal adhesion molecules in living cells by modifying the fluorescence recovery after photobleaching (FRAP) technique and combining it with mathematical modeling. Using this method, we show that decreasing cellular traction forces on focal adhesions by three different techniques--chemical inhibition of Cytoskeletal Tension generation, laser incision of an associated actin stress fiber, or use of compliant extracellular matrices--increases the k(OFF) of the focal adhesion protein zyxin. In contrast, the k(OFF) of another adhesion protein, vinculin, remains unchanged after Tension dissipation. Mathematical models also demonstrate that these force-dependent increases in zyxin's k(OFF) that occur over seconds are sufficient to quantitatively predict large-scale focal adhesion disassembly that occurs physiologically over many minutes. These findings demonstrate that the molecular binding kinetics of some, but not all, focal adhesion proteins are sensitive to mechanical force, and suggest that force-dependent changes in this biophysical parameter may govern the supramolecular events that underlie focal adhesion remodeling in living cells.

  • cellular adaptation to mechanical stress role of integrins rho Cytoskeletal Tension and mechanosensitive ion channels
    Journal of Cell Science, 2006
    Co-Authors: Benjamin D Matthews, Robert Mannix, Darryl R Overby, Donald E Ingber
    Abstract:

    To understand how cells sense and adapt to mechanical stress, we applied Tensional forces to magnetic microbeads bound to cell-surface integrin receptors and measured changes in bead displacement with sub-micrometer resolution using optical microscopy. Cells exhibited four types of mechanical responses: (1) an immediate viscoelastic response; (2) early adaptive behavior characterized by pulse-to-pulse attenuation in response to oscillatory forces; (3) later adaptive cell stiffening with sustained (>15 second) static stresses; and (4) a large-scale repositioning response with prolonged (>1 minute) stress. Importantly, these adaptation responses differed biochemically. The immediate and early responses were affected by chemically dissipating Cytoskeletal prestress (isometric Tension), whereas the later adaptive response was not. The repositioning response was prevented by inhibiting Tension through interference with Rho signaling, similar to the case of the immediate and early responses, but it was also prevented by blocking mechanosensitive ion channels or by inhibiting Src tyrosine kinases. All adaptive responses were suppressed by cooling cells to 4°C to slow biochemical remodeling. Thus, cells use multiple mechanisms to sense and respond to static and dynamic changes in the level of mechanical stress applied to integrins.

  • control of basement membrane remodeling and epithelial branching morphogenesis in embryonic lung by rho and Cytoskeletal Tension
    Developmental Dynamics, 2005
    Co-Authors: Kimberly A Moore, Tom Polte, Sui Huang, Bin Shi, Eben Alsberg, Mary E Sunday, Donald E Ingber
    Abstract:

    Local alterations in the mechanical compliance of the basement membrane that alter the level of isometric Tension in the cell have been postulated to influence tissue morphogenesis. To explore whether cell Tension contributes to tissue pattern formation in vivo, we modulated Cytoskeletal force generation in embryonic mouse lung (embryonic days 12-14) rudiments using inhibitors of Rho-associated kinase (ROCK), myosin light chain kinase, myosin ATPase, and microfilament integrity, or a Rho stimulator (cytotoxic necrotizing factor-1). Tension inhibition resulted in loss of normal differentials in basement membrane thickness, inhibition of new terminal bud formation, and disorganization of epithelial growth patterns as well as disruption of capillary blood vessels. In contrast, increasing cell Tension through Rho activation, as confirmed by quantitation of myosin light chain phosphorylation and immunohistocytochemical analysis of actin organization, accelerated lung branching and increase capillary elongation. These data suggest that changes in Cytoskeletal Tension mediated by Rho signaling through ROCK may play an important role in the establishment of the spatial differentials in cell growth and extracellular matrix remodeling that drive embryonic lung development.

Celeste M Nelson - One of the best experts on this subject based on the ideXlab platform.

  • matrix compliance and rhoa direct the differentiation of mammary progenitor cells
    Biomechanics and Modeling in Mechanobiology, 2012
    Co-Authors: Celeste M Nelson
    Abstract:

    The regenerative capacity of the mammary gland following post-lactational involution depends on the presence of multipotent stem or progenitor cells. Mammary progenitor cells exist as a quiescent and self-renewing population capable of differentiating into luminal epithelial and myoepithelial cells and generating ductal and alveolar structures. The fate choices of these cells are regulated by several soluble signals as well as their surrounding extracellular matrix. Whereas matrix stiffness has been implicated in organ-specific differentiation of embryonic and mesenchymal stem cells, the effects of substratum compliance on the more limited fate switches typical of tissue-specific progenitor cells are unknown. Here, we examined how the mechanical properties of the microenvironment affect the differentiation of mammary progenitor cells. Immortalized human mammary progenitor cells were cultured on synthetic hydrogels of varying stiffness, and their self-renewal and fate decisions were quantified. We found that cells cultured on soft substrata differentiated preferentially into luminal epithelial cells, whereas those cultured on stiff substrata differentiated preferentially into myoepithelial cells. Furthermore, pharmacological manipulations of Cytoskeletal Tension in conjunction with analysis of gene expression revealed that mechanical properties of the microenvironment signal through the small GTPase RhoA and Cytoskeletal contractility to modulate the differentiation of mammary progenitor cells. These data suggest that subtle variations in the mechanical compliance of a tissue can direct the fate decisions of its resident progenitor cells.

  • tissue geometry patterns epithelial mesenchymal transition via intercellular mechanotransduction
    Journal of Cellular Biochemistry, 2010
    Co-Authors: Esther W Gomez, Qike K Chen, Nikolce Gjorevski, Celeste M Nelson
    Abstract:

    Epithelial-mesenchymal transition (EMT) is a phenotypic change in which epithelial cells detach from their neighbors and become motile. Whereas soluble signals such as growth factors and cytokines are responsible for stimulating EMT, here we show that gradients of mechanical stress define the spatial locations at which EMT occurs. When treated with transforming growth factor (TGF)-β, cells at the corners and edges of square mammary epithelial sheets expressed EMT markers, whereas those in the center did not. Changing the shape of the epithelial sheet altered the spatial pattern of EMT. Traction force microscopy and finite element modeling demonstrated that EMT-permissive regions experienced the highest mechanical stress. Myocardin-related transcription factor (MRTF)-A was localized to the nuclei of cells located in high-stress regions, and inhibiting Cytoskeletal Tension or MRTF-A expression abrogated the spatial patterning of EMT. These data suggest a causal role for tissue geometry and endogenous mechanical stresses in the spatial patterning of EMT.

  • vascular endothelial cadherin regulates Cytoskeletal Tension cell spreading and focal adhesions by stimulating rhoa
    Molecular Biology of the Cell, 2004
    Co-Authors: Celeste M Nelson, Dana M Pirone, John L Tan, Christopher S Chen
    Abstract:

    Changes in vascular endothelial (VE)-cadherin-mediated cell-cell adhesion and integrin-mediated cell-matrix adhesion coordinate to affect the physical and mechanical rearrangements of the endothelium, although the mechanisms for such cross talk remain undefined. Herein, we describe the regulation of focal adhesion formation and Cytoskeletal Tension by intercellular VE-cadherin engagement, and the molecular mechanism by which this occurs. Increasing the density of endothelial cells to increase cell-cell contact decreased focal adhesions by decreasing cell spreading. This contact inhibition of cell spreading was blocked by disrupting VE-cadherin engagement with an adenovirus encoding dominant negative VE-cadherin. When changes in cell spreading were prevented by culturing cells on a micropatterned substrate, VE-cadherin-mediated cell-cell contact paradoxically increased focal adhesion formation. We show that VE-cadherin engagement mediates each of these effects by inducing both a transient and sustained activation of RhoA. Both the increase and decrease in cell-matrix adhesion were blocked by disrupting intracellular Tension and signaling through the Rho-ROCK pathway. In all, these findings demonstrate that VE-cadherin signals through RhoA and the actin cytoskeleton to cross talk with cell-matrix adhesion and thereby define a novel pathway by which cell-cell contact alters the global mechanical and functional state of cells.

  • cell shape Cytoskeletal Tension and rhoa regulate stem cell lineage commitment
    Developmental Cell, 2004
    Co-Authors: Rowena Mcbeath, Dana M Pirone, Celeste M Nelson, Kiran Bhadriraju, Christopher S Chen
    Abstract:

    Commitment of stem cells to different lineages is regulated by many cues in the local tissue microenvironment. Here we demonstrate that cell shape regulates commitment of human mesenchymal stem cells (hMSCs) to adipocyte or osteoblast fate. hMSCs allowed to adhere, flatten, and spread underwent osteogenesis, while unspread, round cells became adipocytes. Cell shape regulated the switch in lineage commitment by modulating endogenous RhoA activity. Expressing dominant-negative RhoA committed hMSCs to become adipocytes, while constitutively active RhoA caused osteogenesis. However, the RhoA-mediated adipogenesis or osteogenesis was conditional on a round or spread shape, respectively, while constitutive activation of the RhoA effector, ROCK, induced osteogenesis independent of cell shape. This RhoA-ROCK commitment signal required actin-myosin-generated Tension. These studies demonstrate that mechanical cues experienced in developmental and adult contexts, embodied by cell shape, Cytoskeletal Tension, and RhoA signaling, are integral to the commitment of stem cell fate.

  • cell shape Cytoskeletal Tension and rhoa regulate stem cell lineage commitment
    Developmental Cell, 2004
    Co-Authors: Rowena Mcbeath, Dana M Pirone, Celeste M Nelson, Kiran Bhadriraju, Christopher S Chen
    Abstract:

    Summary cell spreading has been shown to increase osteoblast differentiation in preosteoblastic progenitors as mea- Commitment of stem cells to different lineages is regu- sured by increased osteopontin and osteocalcin expres- lated by many cues in the local tissue microenviron-

Dana M Pirone - One of the best experts on this subject based on the ideXlab platform.

  • activation of rock by rhoa is regulated by cell adhesion shape and Cytoskeletal Tension
    Experimental Cell Research, 2007
    Co-Authors: Kiran Bhadriraju, Dana M Pirone, John L Tan, Michael T Yang, Sami Alom Ruiz, Christopher S Chen
    Abstract:

    Adhesion to the extracellular matrix regulates numerous changes in the actin cytoskeleton by regulating the activity of the Rho family of small GTPases. Here, we report that adhesion and the associated changes in cell shape and Cytoskeletal Tension are all required for GTP-bound RhoA to activate its downstream effector, ROCK. Using an in vitro kinase assay for endogenous ROCK, we found that cells in suspension, attached on substrates coated with low density fibronectin, or on spreading-restrictive micropatterned islands all exhibited low ROCK activity and correspondingly low myosin light chain phosphorylation, in the face of high levels of GTP-bound RhoA. In contrast, allowing cells to spread against substrates rescued ROCK and myosin activity. Interestingly, inhibition of Tension with cytochalasin D or blebbistatin also inhibited ROCK activity within 20 min. The abrogation of ROCK activity by cell detachment or inhibition of Tension could not be rescued by constitutively active RhoA-V14. These results suggest the existence of a feedback loop between Cytoskeletal Tension, adhesion maturation, and ROCK signaling that likely contributes to numerous mechanochemical processes.

  • an inhibitory role for fak in regulating proliferation a link between limited adhesion and rhoa rock signaling
    Journal of Cell Biology, 2006
    Co-Authors: Dana M Pirone, Sami Alom Ruiz, Lin Gao, Wendy F Liu, Srivatsan Raghavan, Christopher A Lemmon, Lewis H Romer, Christopher S Chen
    Abstract:

    Focal adhesion kinase (FAK) transduces cell adhesion to the extracellular matrix into proliferative signals. We show that FAK overexpression induced proliferation in endothelial cells, which are normally growth arrested by limited adhesion. Interestingly, displacement of FAK from adhesions by using a FAK−/− cell line or by expressing the C-terminal fragment FRNK also caused an escape of adhesion-regulated growth arrest, suggesting dual positive and negative roles for FAK in growth regulation. Expressing kinase-dead FAK-Y397F in FAK−/− cells prevented uncontrolled growth, demonstrating the antiproliferative function of inactive FAK. Unlike FAK overexpression–induced growth, loss of growth control in FAK−/− or FRNK-expressing cells increased RhoA activity, Cytoskeletal Tension, and focal adhesion formation. ROCK inhibition rescued adhesion-dependent growth control in these cells, and expression of constitutively active RhoA or ROCK dysregulated growth. These findings demonstrate the ability of FAK to suppress and promote growth, and underscore the importance of multiple mechanisms, even from one molecule, to control cell proliferation.

  • vascular endothelial cadherin regulates Cytoskeletal Tension cell spreading and focal adhesions by stimulating rhoa
    Molecular Biology of the Cell, 2004
    Co-Authors: Celeste M Nelson, Dana M Pirone, John L Tan, Christopher S Chen
    Abstract:

    Changes in vascular endothelial (VE)-cadherin-mediated cell-cell adhesion and integrin-mediated cell-matrix adhesion coordinate to affect the physical and mechanical rearrangements of the endothelium, although the mechanisms for such cross talk remain undefined. Herein, we describe the regulation of focal adhesion formation and Cytoskeletal Tension by intercellular VE-cadherin engagement, and the molecular mechanism by which this occurs. Increasing the density of endothelial cells to increase cell-cell contact decreased focal adhesions by decreasing cell spreading. This contact inhibition of cell spreading was blocked by disrupting VE-cadherin engagement with an adenovirus encoding dominant negative VE-cadherin. When changes in cell spreading were prevented by culturing cells on a micropatterned substrate, VE-cadherin-mediated cell-cell contact paradoxically increased focal adhesion formation. We show that VE-cadherin engagement mediates each of these effects by inducing both a transient and sustained activation of RhoA. Both the increase and decrease in cell-matrix adhesion were blocked by disrupting intracellular Tension and signaling through the Rho-ROCK pathway. In all, these findings demonstrate that VE-cadherin signals through RhoA and the actin cytoskeleton to cross talk with cell-matrix adhesion and thereby define a novel pathway by which cell-cell contact alters the global mechanical and functional state of cells.

  • cell shape Cytoskeletal Tension and rhoa regulate stem cell lineage commitment
    Developmental Cell, 2004
    Co-Authors: Rowena Mcbeath, Dana M Pirone, Celeste M Nelson, Kiran Bhadriraju, Christopher S Chen
    Abstract:

    Commitment of stem cells to different lineages is regulated by many cues in the local tissue microenvironment. Here we demonstrate that cell shape regulates commitment of human mesenchymal stem cells (hMSCs) to adipocyte or osteoblast fate. hMSCs allowed to adhere, flatten, and spread underwent osteogenesis, while unspread, round cells became adipocytes. Cell shape regulated the switch in lineage commitment by modulating endogenous RhoA activity. Expressing dominant-negative RhoA committed hMSCs to become adipocytes, while constitutively active RhoA caused osteogenesis. However, the RhoA-mediated adipogenesis or osteogenesis was conditional on a round or spread shape, respectively, while constitutive activation of the RhoA effector, ROCK, induced osteogenesis independent of cell shape. This RhoA-ROCK commitment signal required actin-myosin-generated Tension. These studies demonstrate that mechanical cues experienced in developmental and adult contexts, embodied by cell shape, Cytoskeletal Tension, and RhoA signaling, are integral to the commitment of stem cell fate.

  • cell shape Cytoskeletal Tension and rhoa regulate stem cell lineage commitment
    Developmental Cell, 2004
    Co-Authors: Rowena Mcbeath, Dana M Pirone, Celeste M Nelson, Kiran Bhadriraju, Christopher S Chen
    Abstract:

    Summary cell spreading has been shown to increase osteoblast differentiation in preosteoblastic progenitors as mea- Commitment of stem cells to different lineages is regu- sured by increased osteopontin and osteocalcin expres- lated by many cues in the local tissue microenviron-

Kiran Bhadriraju - One of the best experts on this subject based on the ideXlab platform.

  • activation of rock by rhoa is regulated by cell adhesion shape and Cytoskeletal Tension
    Experimental Cell Research, 2007
    Co-Authors: Kiran Bhadriraju, Dana M Pirone, John L Tan, Michael T Yang, Sami Alom Ruiz, Christopher S Chen
    Abstract:

    Adhesion to the extracellular matrix regulates numerous changes in the actin cytoskeleton by regulating the activity of the Rho family of small GTPases. Here, we report that adhesion and the associated changes in cell shape and Cytoskeletal Tension are all required for GTP-bound RhoA to activate its downstream effector, ROCK. Using an in vitro kinase assay for endogenous ROCK, we found that cells in suspension, attached on substrates coated with low density fibronectin, or on spreading-restrictive micropatterned islands all exhibited low ROCK activity and correspondingly low myosin light chain phosphorylation, in the face of high levels of GTP-bound RhoA. In contrast, allowing cells to spread against substrates rescued ROCK and myosin activity. Interestingly, inhibition of Tension with cytochalasin D or blebbistatin also inhibited ROCK activity within 20 min. The abrogation of ROCK activity by cell detachment or inhibition of Tension could not be rescued by constitutively active RhoA-V14. These results suggest the existence of a feedback loop between Cytoskeletal Tension, adhesion maturation, and ROCK signaling that likely contributes to numerous mechanochemical processes.

  • cell shape Cytoskeletal Tension and rhoa regulate stem cell lineage commitment
    Developmental Cell, 2004
    Co-Authors: Rowena Mcbeath, Dana M Pirone, Celeste M Nelson, Kiran Bhadriraju, Christopher S Chen
    Abstract:

    Commitment of stem cells to different lineages is regulated by many cues in the local tissue microenvironment. Here we demonstrate that cell shape regulates commitment of human mesenchymal stem cells (hMSCs) to adipocyte or osteoblast fate. hMSCs allowed to adhere, flatten, and spread underwent osteogenesis, while unspread, round cells became adipocytes. Cell shape regulated the switch in lineage commitment by modulating endogenous RhoA activity. Expressing dominant-negative RhoA committed hMSCs to become adipocytes, while constitutively active RhoA caused osteogenesis. However, the RhoA-mediated adipogenesis or osteogenesis was conditional on a round or spread shape, respectively, while constitutive activation of the RhoA effector, ROCK, induced osteogenesis independent of cell shape. This RhoA-ROCK commitment signal required actin-myosin-generated Tension. These studies demonstrate that mechanical cues experienced in developmental and adult contexts, embodied by cell shape, Cytoskeletal Tension, and RhoA signaling, are integral to the commitment of stem cell fate.

  • cell shape Cytoskeletal Tension and rhoa regulate stem cell lineage commitment
    Developmental Cell, 2004
    Co-Authors: Rowena Mcbeath, Dana M Pirone, Celeste M Nelson, Kiran Bhadriraju, Christopher S Chen
    Abstract:

    Summary cell spreading has been shown to increase osteoblast differentiation in preosteoblastic progenitors as mea- Commitment of stem cells to different lineages is regu- sured by increased osteopontin and osteocalcin expres- lated by many cues in the local tissue microenviron-

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