Matrix elasticity directs stem cell lineage specification.

doi:10.1016/J.CELL.2006.06.044

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Matrix elasticity directs stem cell lineage specification.

Journal Article•DOI•

Matrix elasticity directs stem cell lineage specification.

Adam J. Engler¹, Shamik Sen¹, H. Lee Sweeney¹, Dennis E. Discher•Institutions (1)

University of Pennsylvania¹

25 Aug 2006-Cell (Cell Press)-Vol. 126, Iss: 4, pp 677-689

TL;DR: Naive mesenchymal stem cells are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types.

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About: This article is published in Cell.The article was published on 2006-08-25 and is currently open access. It has received 12204 citations till now. The article focuses on the topics: Mesenchymal stem cell differentiation & Stem cell fate determination.

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Journal Article•DOI•

Role of YAP/TAZ in mechanotransduction

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Sirio Dupont¹, Leonardo Morsut¹, Mariaceleste Aragona¹, Elena Enzo¹, Stefano Giulitti¹, Michelangelo Cordenonsi¹, Francesca Zanconato¹, Jimmy Le Digabel², Mattia Forcato³, Silvio Bicciato³, Nicola Elvassore¹, Stefano Piccolo¹ - Show less +8 more•Institutions (3)

University of Padua¹, Paris Diderot University², University of Modena and Reggio Emilia³

09 Jun 2011-Nature

TL;DR: YAP/TAZ are identified as sensors and mediators of mechanical cues instructed by the cellular microenvironment and are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry.

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Abstract: Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.

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4,120 citations

Journal Article•DOI•

Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling

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Kandice R. Levental¹, Hongmei Yu², Laura Kass², Johnathon N. Lakins², Mikala Egeblad², Janine T. Erler³, Sheri F. T. Fong⁴, Katalin Csiszar⁴, Amato J. Giaccia³, Wolfgang Weninger⁵, Mitsuo Yamauchi⁶, David L. Gasser¹, Valerie M. Weaver - Show less +9 more•Institutions (6)

University of Pennsylvania¹, University of California, San Francisco², Stanford University³, University of Hawaii at Manoa⁴, Wistar Institute⁵, University of North Carolina at Chapel Hill⁶

25 Nov 2009-Cell

TL;DR: Reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence, and data show how collagenCrosslinking can modulate tissue fibrosis and stiffness to force focal adhesion, growth factor signaling and breast malignancies.

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3,396 citations

Journal Article•DOI•

The Extracellular Matrix: Not Just Pretty Fibrils

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Richard O. Hynes¹•Institutions (1)

Massachusetts Institute of Technology¹

27 Nov 2009-Science

TL;DR: The extracellular matrix and ECM proteins are important in phenomena as diverse as developmental patterning, stem cell niches, cancer, and genetic diseases and these properties need to be incorporated into considerations of the functions of the ECM.

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Abstract: The extracellular matrix (ECM) and ECM proteins are important in phenomena as diverse as developmental patterning, stem cell niches, cancer, and genetic diseases. The ECM has many effects beyond providing structural support. ECM proteins typically include multiple, independently folded domains whose sequences and arrangement are highly conserved. Some of these domains bind adhesion receptors such as integrins that mediate cell-matrix adhesion and also transduce signals into cells. However, ECM proteins also bind soluble growth factors and regulate their distribution, activation, and presentation to cells. As organized, solid-phase ligands, ECM proteins can integrate complex, multivalent signals to cells in a spatially patterned and regulated fashion. These properties need to be incorporated into considerations of the functions of the ECM.

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2,858 citations

Journal Article•DOI•

Biomaterials & scaffolds for tissue engineering

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Fergal J. O'Brien¹•Institutions (1)

Royal College of Surgeons in Ireland¹

01 Mar 2011-Materials Today

TL;DR: The functional requirements, and types, of materials used in developing state of the art of scaffolds for tissue engineering applications are described and where future research and direction is required are described.

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2,648 citations

Journal Article•DOI•

Designing hydrogels for controlled drug delivery.

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Jianyu Li¹, David J. Mooney¹•Institutions (1)

Wyss Institute for Biologically Inspired Engineering¹

18 Oct 2016-Nature Reviews Materials

TL;DR: This Review discusses how different mechanisms interact and can be integrated to exert fine control in time and space over the drug presentation, and collects experimental release data from the literature and presents quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems.

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Abstract: Hydrogel delivery systems can leverage therapeutically beneficial outcomes of drug delivery and have found clinical use. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including small-molecule drugs, macromolecular drugs and cells. Owing to their tunable physical properties, controllable degradability and capability to protect labile drugs from degradation, hydrogels serve as a platform in which various physiochemical interactions with the encapsulated drugs control their release. In this Review, we cover multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on physical and chemical properties of the hydrogel network and the hydrogel-drug interactions across the network, mesh, and molecular (or atomistic) scales. We discuss how different mechanisms interact and can be integrated to exert fine control in time and space over the drug presentation. We also collect experimental release data from the literature, review clinical translation to date of these systems, and present quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems.

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2,457 citations

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References

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Journal Article•DOI•

Specificity of blebbistatin, an inhibitor of myosin II.

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John Limouze¹, Aaron F. Straight², Timothy J. Mitchison², James R. Sellers¹•Institutions (2)

National Institutes of Health¹, Harvard University²

01 Jan 2004-Journal of Muscle Research and Cell Motility

TL;DR: The specificity and potency of Blebbistatin are examined by assaying its effects on the actin-activated MgATPase assay of diverse members of the myosin superfamily, and smooth muscle which is highly homologous to vertebrate nonmuscle myOSin is only poorly inhibited.

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Abstract: Blebbistatin is a small molecule inhibitor discovered in a screen for inhibitors of nonmuscle myosin IIA. We have examined the specificity and potency of the drug by assaying its effects on the actin-activated MgATPase assay of diverse members of the myosin superfamily. Blebbistatin potently inhibits several striated muscle myosins as well as vertebrate nonmuscle myosin IIA and IIB with IC50 values ranging from 0.5 to 5 μM. Interestingly, smooth muscle which is highly homologous to vertebrate nonmuscle myosin is only poorly inhibited (IC50=80 μM). The drug potently inhibits Dictyostelium myosin II, but poorly inhibits Acanthamoeba myosin II. Blebbistatin did not inhibit representative myosin superfamily members from classes I, V, and X.

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375 citations

"Matrix elasticity directs stem cell..." refers background in this paper

...Chronic inhibition of NMM II’s ATPase activity with blebbistatin (Limouze et al., 2004; Straight et al., 2003) not only inhibits morphological changes of MSCs on various matrices (Figures 1Bi and 1Bii) but also reduces transcripts levels for NMM IIA (to 50%), IIB (to 8%), and IIC (to 3...
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...…Sweeney,1 and Dennis E. Discher1,2,3,4,* 1Pennsylvania Muscle Institute 2School of Engineering and Applied Science 3Cell & Molecular Biology Graduate Group 4Physics Graduate Group University of Pennsylvania, Philadelphia, PA 19104, USA *Contact: discher@seas.upenn.edu DOI 10.1016/j.cell.2006.06.044...
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...All of the NMM II isoforms are inhibited by blebbistatin, which does not inhibit any other myosin found in MSCs (see below), other than myosin VI (Limouze et al., 2004)....
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...…in vertebrate cells without affecting MLCK. Crystal structures show inhibition of actin-activated ATPase activity by blebbistatin (Allingham et al., 2005) requires a specific alanine (or serine) residue that is found only in class II and VI myosins (Limouze et al., 2004; Straight et al., 2003)....
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Journal Article•DOI•

Application of the micropipette technique to the measurement of cultured porcine aortic endothelial cell viscoelastic properties.

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M. Sato¹, D. P. Theret², L. T. Wheeler², Norio Ohshima¹, Robert M. Nerem³ - Show less +1 more•Institutions (3)

University of Tsukuba¹, University of Houston², Georgia Institute of Technology³

01 Aug 1990-Journal of Biomechanical Engineering-transactions of The Asme

TL;DR: The actin microfilaments were found to be the major cytoskeletal component determining the viscoelastic response of endothelial cells grown in static culture.

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Abstract: The viscoelastic deformation of porcine aortic endothelial cells grown under static culture conditions was measured using the micropipette technique. Experiments were conducted both for control cells (mechanically or trypsin detached from the substrate) and for cells in which cytoskeletal elements were disrupted by cytochalasin B or colchicine. The time course of the aspirated length into the pipette was measured after applying a stepwise increase in aspiration pressure. To analyze the data, a standard linear viscoelastic half-space model of the endothelial cell was used. The aspirated length was expressed as an exponential function of time. The actin microfilaments were found to be the major cytoskeletal component determining the viscoelastic response of endothelial cells grown in static culture.

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374 citations

Journal Article•DOI•

Surface probe measurements of the elasticity of sectioned tissue, thin gels and polyelectrolyte multilayer films : correlations between substrate stiffness and cell adhesion

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Adam J. Engler¹, Ludovic Richert², Joyce Wong³, Catherine Picart², Dennis E. Discher¹ - Show less +1 more•Institutions (3)

University of Pennsylvania¹, French Institute of Health and Medical Research², Boston University³

10 Oct 2004-Surface Science

TL;DR: In this article, sectioned arteries were probed by atomic force microscopy (AFM) within the smooth muscle cell (SMC)-rich medial layer, yielding an apparent Youngs modulus Emedia � 5-8 kPa.

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371 citations

"Matrix elasticity directs stem cell..." refers background or methods or result in this paper

...AFM for Matrix Elasticity and Cell Mechanics Methods Substrate elasticity was characterized per Engler et al. (2004b)....
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...Substrate elasticity was characterized per Engler et al. (2004b) ....
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...Cell Culture Human Mesenchymal Stem Cells (MSCs; Osiris Therapeutics; Baltimore, MD), human osteoblasts (hFOBs, ATCC), primary human skin fibroblasts (1F7) (Engler et al., 2004a), and murine myoblasts (C2C12s, ATCC) were cultured in normal growth media listed in Table S2....
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...Forces generated and/or imposed on the cell’s actin cytoskeleton have been postulated to influence differentiation (Engler et al., 2004a; Hinz et al., 2001; McBeath et al., 2004), but no past reports have hinted at strong, tissuedirected feedback of microenvironment elasticity on myosin expression…...
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...and coworkers was used ( Engler et al., 2004b )....
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Journal Article•DOI•

Fibronectin extension and unfolding within cell matrix fibrils controlled by cytoskeletal tension

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Gretchen Baneyx¹, Loren Baugh, Viola Vogel•Institutions (1)

University of Washington¹

16 Apr 2002-Proceedings of the National Academy of Sciences of the United States of America

TL;DR: The results suggest that cell-generated force is required to maintain Fn in partially unfolded conformations, and support a model of Fn fibril elasticity based on unraveling and refolding of FnIII modules.

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Abstract: Evidence is emerging that mechanical stretching can alter the functional states of proteins. Fibronectin (Fn) is a large, extracellular matrix protein that is assembled by cells into elastic fibrils and subjected to contractile forces. Assembly into fibrils coincides with expression of biological recognition sites that are buried in Fn's soluble state. To investigate how supramolecular assembly of Fn into fibrillar matrix enables cells to mechanically regulate its structure, we used fluorescence resonance energy transfer (FRET) as an indicator of Fn conformation in the fibrillar matrix of NIH 3T3 fibroblasts. Fn was randomly labeled on amine residues with donor fluorophores and site-specifically labeled on cysteine residues in modules FnIII7 and FnIII15 with acceptor fluorophores. Intramolecular FRET was correlated with known structural changes of Fn in denaturing solution, then applied in cell culture as an indicator of Fn conformation within the matrix fibrils of NIH 3T3 fibroblasts. Based on the level of FRET, Fn in many fibrils was stretched by cells so that its dimer arms were extended and at least one FnIII module unfolded. When cytoskeletal tension was disrupted using cytochalasin D, FRET increased, indicating refolding of Fn within fibrils. These results suggest that cell-generated force is required to maintain Fn in partially unfolded conformations. The results support a model of Fn fibril elasticity based on unraveling and refolding of FnIII modules. We also observed variation of FRET between and along single fibrils, indicating variation in the degree of unfolding of Fn in fibrils. Molecular mechanisms by which mechanical force can alter the structure of Fn, converting tensile forces into biochemical cues, are discussed.

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359 citations

Journal Article•DOI•

Defects in cell adhesion and the visceral endoderm following ablation of nonmuscle myosin heavy chain II-A in mice.

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Mary Anne Conti¹, Sharona Even-Ram¹, Chengyu Liu¹, Kenneth M. Yamada¹, Robert S. Adelstein¹ - Show less +1 more•Institutions (1)

National Institutes of Health¹

01 Oct 2004-Journal of Biological Chemistry

TL;DR: It is shown that mice ablated for NMHC II-A fail to develop a normal patterned embryo with a polarized visceral endoderm by E6.5 and die by E7.5, suggesting an essential role for a single, specific nonmuscle myosin isoform in maintaining cell-cell adhesions in the early mammalian embryo.

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331 citations

"Matrix elasticity directs stem cell..." refers result in this paper

...…August 25, 2006 ª2006 Elsevier Inc. 685 generalizes the matrix-driven assembly of the cytoskeleton to MSCs. NMM II is already known to promote the assembly of focal adhesions (Conti et al., 2004), and so the prominent adhesions on stiffer substrates is consistent with greater activity of NMM II....
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...NMM II is already known to promote the assembly of focal adhesions (Conti et al., 2004), and so the prominent adhesions on stiffer substrates is consistent with greater activity of NMM II....
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