@article {266, title = {MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis.}, journal = {Dev Cell}, volume = {25}, year = {2013}, month = {2013 May 28}, pages = {402-16}, abstract = {

In vitro, topographical and biophysical cues arising from the extracellular matrix (ECM) direct skeletal stem cell (SSC) commitment and differentiation. However, the mechanisms by which the SSC-ECM interface is regulated and the outcome of such interactions on stem cell fate in vivo remain unknown. Here we demonstrate that conditional deletion of the membrane-anchored metalloproteinase MT1-MMP (Mmp14) in mesenchymal progenitors, but not in committed osteoblasts, redirects SSC fate decisions from osteogenesis to adipo- and chondrogenesis. By effecting ECM remodeling, MT1-MMP regulates stem cell shape, thereby activating a β1-integrin/RhoGTPase signaling cascade and triggering the nuclear localization of the transcriptional coactivators YAP and TAZ, which serve to control SSC lineage commitment. These data identify a critical MT1-MMP/integrin/YAP/TAZ axis operative in the stem cell niche that oversees SSC fate determination.

}, keywords = {Adaptor Proteins, Signal Transducing, Adipogenesis, Animals, Antigens, CD29, Bone Marrow Cells, Cell Lineage, Cell Nucleus, Cell Shape, Cells, Cultured, Chondrogenesis, Extracellular Matrix, Gene Knock-In Techniques, Humans, Matrix Metalloproteinase 14, Mesenchymal Stromal Cells, Mice, Mice, Inbred C57BL, Mice, Transgenic, Osteogenesis, Phenotype, Phosphoproteins, Proteolysis, Signal Transduction, Stem Cell Niche, Transcription Factors, Transcriptional Activation}, issn = {1878-1551}, doi = {10.1016/j.devcel.2013.04.011}, author = {Tang, Yi and Rowe, R Grant and Botvinick, Elliot L and Kurup, Abhishek and Putnam, Andrew J and Seiki, Motoharu and Weaver, Valerie M and Keller, Evan T and Goldstein, Steven and Dai, Jinlu and Begun, Dana and Saunders, Thomas and Weiss, Stephen J} } @article {231, title = {Scanning angle interference microscopy reveals cell dynamics at the nanoscale.}, journal = {Nat Methods}, volume = {9}, year = {2012}, month = {2012 Aug}, pages = {825-7}, abstract = {

Emerging questions in cell biology necessitate nanoscale imaging in live cells. Here we present scanning angle interference microscopy, which is capable of localizing fluorescent objects with nanoscale precision along the optical axis in motile cellular structures. We use this approach to resolve nanotopographical features of the cell membrane and cytoskeleton as well as the temporal evolution, three-dimensional architecture and nanoscale dynamics of focal adhesion complexes.

}, keywords = {Cell Membrane, Cells, Cultured, Cytoskeleton, Epithelial Cells, Fibronectins, Focal Adhesions, Humans, Microscopy, Interference, Nanotechnology}, issn = {1548-7105}, doi = {10.1038/nmeth.2077}, author = {Paszek, Matthew J and DuFort, Christopher C and Rubashkin, Matthew G and Davidson, Michael W and Thorn, Kurt S and Liphardt, Jan T and Weaver, Valerie M} } @article {311, title = {Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth.}, journal = {Cancer Cell}, volume = {19}, year = {2011}, month = {2011 Jun 14}, pages = {776-91}, abstract = {

Tumors and associated stroma manifest mechanical properties that promote cancer. Mechanosensation of tissue stiffness activates the Rho/ROCK pathway to increase actomyosin-mediated cellular tension to re-establish force equilibrium. To determine how actomyosin tension affects tissue homeostasis and tumor development, we expressed conditionally active ROCK2 in mouse skin. ROCK activation elevated tissue stiffness via increased collagen. β-catenin, a key element of mechanotranscription pathways, was stabilized by ROCK activation leading to nuclear accumulation, transcriptional activation, and consequent hyperproliferation and skin thickening. Inhibiting actomyosin contractility by blocking LIMK or myosin ATPase attenuated these responses, as did FAK inhibition. Tumor number, growth, and progression were increased by ROCK activation, while ROCK blockade was inhibitory, implicating actomyosin-mediated cellular tension and consequent collagen deposition as significant tumor promoters.

}, keywords = {Actomyosin, Animals, beta Catenin, Biomechanical Phenomena, Cell Proliferation, Cells, Cultured, Epidermis, Humans, Hyperplasia, Mice, Papilloma, rho-Associated Kinases, Signal Transduction, Skin Neoplasms}, issn = {1878-3686}, doi = {10.1016/j.ccr.2011.05.008}, author = {Samuel, Michael S and Lopez, Jose I and McGhee, Ewan J and Croft, Daniel R and Strachan, David and Timpson, Paul and Munro, June and Schr{\"o}der, Ewald and Zhou, Jing and Brunton, Valerie G and Barker, Nick and Clevers, Hans and Sansom, Owen J and Anderson, Kurt I and Weaver, Valerie M and Olson, Michael F} } @article {346, title = {Effect of substrate stiffness and PDGF on the behavior of vascular smooth muscle cells: implications for atherosclerosis.}, journal = {J Cell Physiol}, volume = {225}, year = {2010}, month = {2010 Oct}, pages = {115-22}, abstract = {

Vascular disease, such as atherosclerosis, is accompanied by changes in the mechanical properties of the vessel wall. Although altered mechanics is thought to contribute to disease progression, the molecular mechanisms whereby vessel wall stiffening could promote vascular occlusive disease remain unclear. It is well known that platelet-derived growth factor (PDGF) is a major stimulus for the abnormal migration and proliferation of vascular smooth muscle cells (VSMCs) and contributes critically to vascular disease. Here we used engineered substrates with tunable mechanical properties to explore the effect of tissue stiffness on PDGF signaling in VSMCs as a potential mechanism whereby vessel wall stiffening could promote vascular disease. We found that substrate stiffness significantly enhanced PDGFR activity and VSMC proliferation. After ligand binding, PDGFR followed distinct routes of activation in cells cultured on stiff versus soft substrates, as demonstrated by differences in its intensity and duration of activation, sensitivity to cholesterol extracting agent, and plasma membrane localization. Our results suggest that stiffening of the vessel wall could actively promote pathogenesis of vascular disease by enhancing PDGFR signaling to drive VSMC growth and survival.

}, keywords = {Acrylic Resins, Animals, Atherosclerosis, Cattle, Cell Culture Techniques, Cell Movement, Cell Proliferation, Cells, Cultured, Elasticity, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Platelet-Derived Growth Factor, Receptors, Platelet-Derived Growth Factor}, issn = {1097-4652}, doi = {10.1002/jcp.22202}, author = {Brown, Xin Q and Bartolak-Suki, Erzsebet and Williams, Corin and Walker, Mathew L and Weaver, Valerie M and Wong, Joyce Y} } @article {571, title = {Degradation of nuclear matrix and DNA cleavage in apoptotic thymocytes.}, journal = {J Cell Sci}, volume = {109 ( Pt 1)}, year = {1996}, month = {1996 Jan}, pages = {45-56}, abstract = {

In dexamethasone-treated thymocyte cultures an increase in nuclear proteolytic activity paralleled chromatin fragmentation and the appearance of small apoptotic cells. The elevation of nuclear proteolytic activity was accompanied by site-specific degradation of nuclear mitotic apparatus protein and lamin B, two essential components of the nuclear matrix. Nuclear mitotic apparatus protein phosphorylation and cleavage into 200 and 48 kDa fragments occurred within 30 minutes of dexamethasone treatment. Cleavage of lamin B, which generated a fragment of 46 kDa consistent with the central rod domain of the protein, was also detected after 30 minutes of exposure to the steroid hormone. The level of lamin B phosphorylation did not change as a result of the dexamethasone treatment and the lamina did not solubilize until the later stages of apoptosis. Initial DNA breaks, detected by the terminal transferase-mediated dUTP-biotin nick end labeling assay, occurred throughout the nuclei and solubilization of lamina was not required for this process to commence. The data presented in this paper support a model of apoptotic nuclear destruction brought about by the site-specific proteolysis of key structural proteins. Both the nuclear mitotic apparatus protein and lamin B were specifically targeted by protease(s) at early stages of the cell death pathway, which possibly initiate the cascade of degradative events in apoptosis.

}, keywords = {alpha 1-Antichymotrypsin, Animals, Apoptosis, Cell Nucleus, Cells, Cultured, Dexamethasone, DNA, DNA Damage, Endopeptidases, Lamin Type B, Lamins, Male, Microscopy, Electron, Nuclear Matrix, Nuclear Proteins, Rats, Rats, Sprague-Dawley, Spindle Apparatus, Thymus Gland, Time Factors}, issn = {0021-9533}, author = {Weaver, V M and Carson, C E and Walker, P R and Chaly, N and Lach, B and Raymond, Y and Brown, D L and Sikorska, M} }