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Journal ArticleDOI

Matrix elasticity directs stem cell lineage specification.

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.
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.
Citations
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Journal ArticleDOI
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.
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.

4,120 citations

Journal ArticleDOI
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.

3,396 citations

Journal ArticleDOI
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.
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.

2,858 citations

Journal ArticleDOI
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.

2,648 citations

Journal ArticleDOI
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.
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.

2,457 citations

References
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Journal ArticleDOI
02 Apr 1999-Science
TL;DR: Adult stem cells isolated from marrow aspirates of volunteer donors could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages.
Abstract: Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.

20,479 citations


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

  • ...…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...

    [...]

  • ...…specification of naive stem cells induced by soluble stimuli has been well described (Gang et al., 2004; Jaiswal et al., 1997; McBeath et al., 2004; Pittenger et al., 1999), but the results here report a strong and previously undocumented influence of microenvironment stiffness on stem cell…...

    [...]

  • ...The myoblast induction media used here (MIM, Table S2) is already known to promote myogenesis, with expression of MyoD, Myogenin, and skeletal muscle myosin heavy chain (Gang et al., 2004; Pittenger et al., 1999)....

    [...]

  • ...Naive mesenchymal stem cells (MSCs) are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissuelevel elasticity....

    [...]

  • ...…and have indeed been reported to differentiate into various anchorage-dependent cell types, including neurons, myoblasts, and osteoblasts (respectively, [Deng et al., 2005; Hofstetter et al., 2002; Kondo et al., 2005], [Pittenger et al., 1999], and [McBeath et al., 2004; Pittenger et al., 1999])....

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Journal ArticleDOI
18 Nov 2005-Science
TL;DR: An understanding of how tissue cells—including fibroblasts, myocytes, neurons, and other cell types—sense matrix stiffness is just emerging with quantitative studies of cells adhering to gels with which elasticity can be tuned to approximate that of tissues.
Abstract: Normal tissue cells are generally not viable when suspended in a fluid and are therefore said to be anchorage dependent. Such cells must adhere to a solid, but a solid can be as rigid as glass or softer than a baby's skin. The behavior of some cells on soft materials is characteristic of important phenotypes; for example, cell growth on soft agar gels is used to identify cancer cells. However, an understanding of how tissue cells-including fibroblasts, myocytes, neurons, and other cell types-sense matrix stiffness is just emerging with quantitative studies of cells adhering to gels (or to other cells) with which elasticity can be tuned to approximate that of tissues. Key roles in molecular pathways are played by adhesion complexes and the actinmyosin cytoskeleton, whose contractile forces are transmitted through transcellular structures. The feedback of local matrix stiffness on cell state likely has important implications for development, differentiation, disease, and regeneration.

5,889 citations


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

  • ...Such a wide variation in matrix stiffness for differentiated cells is known to influence focal-adhesion structure and the cytoskeleton (Bershadsky et al., 2003; Cukierman et al., 2001; Discher et al., 2005; Engler et al., 2004a; Lo et al., 2000; Pelham and Wang, 1997)....

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Journal ArticleDOI
TL;DR: The first free, open-source system designed for flexible, high-throughput cell image analysis, CellProfiler is described, which can address a variety of biological questions quantitatively.
Abstract: Biologists can now prepare and image thousands of samples per day using automation, enabling chemical screens and functional genomics (for example, using RNA interference). Here we describe the first free, open-source system designed for flexible, high-throughput cell image analysis, CellProfiler. CellProfiler can address a variety of biological questions quantitatively, including standard assays (for example, cell count, size, per-cell protein levels) and complex morphological assays (for example, cell/organelle shape or subcellular patterns of DNA or protein staining).

4,578 citations

Journal ArticleDOI
TL;DR: It is demonstrated that cell shape regulates commitment of human mesenchymal stem cells to adipocyte or osteoblast fate and 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.

3,995 citations


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

  • ...Similar results as above are found with a standard osteoblast induction media (OIM), which is known to promote cytoskeletal rearrangement and alkaline phosphatase production (Jaiswal et al., 1997; McBeath et al., 2004)....

    [...]

  • ...Lineage specification of naive stem cells induced by soluble stimuli has been well described (Gang et al., 2004; Jaiswal et al., 1997; McBeath et al., 2004; Pittenger et al., 1999), but the results here report a strong and previously undocumented influence of microenvironment stiffness on stem cell…...

    [...]

  • ...(McBeath et al., 2004; Wang et al., 2002)....

    [...]

  • ...Myosins in MSCs Couple Expression to Matrix Stiffness and Reveal a Key Role for NMM IIs 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 or stem cell lineage specification....

    [...]

  • ...Lineage specification of naive stem cells induced by soluble stimuli has been well described (Gang et al., 2004; Jaiswal et al., 1997; McBeath et al., 2004; Pittenger et al., 1999), but the results here report a strong and previously undocumented influence of microenvironment stiffness on stem cell specification....

    [...]

Journal ArticleDOI
TL;DR: It is clear that the understanding of the myofibroblast — its origins, functions and molecular regulation — will have a profound influence on the future effectiveness not only of tissue engineering but also of regenerative medicine generally.
Abstract: During the past 20 years, it has become generally accepted that the modulation of fibroblastic cells towards the myofibroblastic phenotype, with acquisition of specialized contractile features, is essential for connective-tissue remodelling during normal and pathological wound healing. Yet the myofibroblast still remains one of the most enigmatic of cells, not least owing to its transient appearance in association with connective-tissue injury and to the difficulties in establishing its role in the production of tissue contracture. It is clear that our understanding of the myofibroblast its origins, functions and molecular regulation will have a profound influence on the future effectiveness not only of tissue engineering but also of regenerative medicine generally.

3,836 citations


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

  • ...…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...

    [...]

  • ...…gels and wrinkling-silicone sheets also suggest some responsiveness to the physical state of the matrix (Hinz et al., 2001; Nakagawa et al., 1989; Tomasek et al., 2002; Wozniak et al., 2003), but gel porosity and film topography complicate identification of possible contributions of substrate…...

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