Authors: Shaohe Wang, Kazue Matsumoto, Samantha R Lish...

Many embryonic organs undergo epithelial morphogenesis to form tree-like hierarchical structures. However, it remains unclear what drives the budding and branching of stratified epithelia, such as in the embryonic salivary gland and pancreas. Here, we performed live-organ imaging of mouse embryonic salivary glands at single-cell resolution to reveal that budding morphogenesis is driven by expansion and folding of a distinct epithelial surface cell sheet characterized by strong cell-matrix adhesions and weak cell-cell adhesions. Profiling of single-cell transcriptomes of this epithelium revealed spatial patterns of transcription underlying these cell adhesion differences. We then synthetically reconstituted budding morphogenesis by experimentally suppressing E-cadherin expression and inducing basement membrane formation in 3D spheroid cultures of engineered cells, which required β1-integrin-mediated cell-matrix adhesion for successful budding. Thus, stratified epithelial budding, the key first step of branching morphogenesis, is driven by an overall combination of strong cell-matrix adhesion and weak cell-cell adhesion by peripheral epithelial cells.

Topics: Animals; Basement Membrane; Cell Adhesion; Cell Division; Cell Movement; Cell Tracking; Cell-Matrix Junctions; Embryo, Mammalian; Epithelial Cells; Epithelium; Gene Expression Regulation, Developmental; HEK293 Cells; Humans; Integrins; Mice; Models, Biological; Morphogenesis; Salivary Glands; Transcriptome

PubMed: 34133940
DOI: 10.1016/j.cell.2021.05.015

Authors: Patrizia Romani, Nunzia Nirchio, Mattia Arboit...

Metastatic breast cancer cells disseminate to organs with a soft microenvironment. Whether and how the mechanical properties of the local tissue influence their response to treatment remains unclear. Here we found that a soft extracellular matrix empowers redox homeostasis. Cells cultured on a soft extracellular matrix display increased peri-mitochondrial F-actin, promoted by Spire1C and Arp2/3 nucleation factors, and increased DRP1- and MIEF1/2-dependent mitochondrial fission. Changes in mitochondrial dynamics lead to increased production of mitochondrial reactive oxygen species and activate the NRF2 antioxidant transcriptional response, including increased cystine uptake and glutathione metabolism. This retrograde response endows cells with resistance to oxidative stress and reactive oxygen species-dependent chemotherapy drugs. This is relevant in a mouse model of metastatic breast cancer cells dormant in the lung soft tissue, where inhibition of DRP1 and NRF2 restored cisplatin sensitivity and prevented disseminated cancer-cell awakening. We propose that targeting this mitochondrial dynamics- and redox-based mechanotransduction pathway could open avenues to prevent metastatic relapse.

Topics: Actin-Related Protein 2-3 Complex; Actins; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Transformed; Cell Line, Tumor; Cell-Matrix Junctions; Drug Resistance, Neoplasm; Dynamins; Energy Metabolism; Extracellular Matrix; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mechanotransduction, Cellular; Mice, Inbred BALB C; Microfilament Proteins; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; NF-E2-Related Factor 2; Nuclear Proteins; Oxidation-Reduction; Oxidative Stress; Peptide Elongation Factors; Tumor Microenvironment; Mice

PubMed: 35165418
DOI: 10.1038/s41556-022-00843-w

Authors: Patrizia Romani, Irene Brian, Giulia Santinon...

Extracellular matrix (ECM) mechanical cues have powerful effects on cell proliferation, differentiation and death. Here, starting from an unbiased metabolomics approach, we identify synthesis of neutral lipids as a general response to mechanical signals delivered by cell-matrix adhesions. Extracellular physical cues reverberate on the mechanical properties of the Golgi apparatus and regulate the Lipin-1 phosphatidate phosphatase. Conditions of reduced actomyosin contractility lead to inhibition of Lipin-1, accumulation of SCAP/SREBP to the Golgi apparatus and activation of SREBP transcription factors, in turn driving lipid synthesis and accumulation. This occurs independently of YAP/TAZ, mTOR and AMPK, and in parallel to feedback control by sterols. Regulation of SREBP can be observed in a stiffened diseased tissue, and contributes to the pro-survival activity of ROCK inhibitors in pluripotent stem cells. We thus identify a general mechanism centered on Lipin-1 and SREBP that links the physical cell microenvironment to a key metabolic pathway.

Topics: Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell-Matrix Junctions; Cellular Microenvironment; Cues; Extracellular Matrix; Golgi Apparatus; Humans; Lipid Metabolism; Metabolomics; Phosphatidate Phosphatase; Signal Transduction; Sterol Regulatory Element Binding Proteins

PubMed: 30718857
DOI: 10.1038/s41556-018-0270-5

Authors: Toshiyuki Murai, Hiroto Kawashima, David Naor...

Topics: Animals; Cell Adhesion; Cell-Matrix Junctions; Humans; Neoplasms

PubMed: 32038639
DOI: 10.3389/fimmu.2019.03126

Authors: Mengshi Lei, Weiyou Wang, Hong Zhang...

The dorsal root ganglion (DRG) is characterized by the dense clustering of primary sensory neuron bodies, with their axons extending to target tissues for sensory perception. The close physical proximity of DRG neurons facilitates the integration and amplification of somatosensation, ensuring normal physiological functioning. However, the mechanism underlying DRG neuron aggregation was unclear. In our study, we culture DRG neurons from newborn rats on substrates with varying stiffness and observe that the aggregation of DRG neurons is influenced by mechanical signals arising from substrate stiffness. Moreover, we identify Piezo1 as the mechanosensor responsible for DRG neurons' ability to sense different substrate stiffness. We further demonstrate that the Piezo1-calpain-integrin-β1/E-cadherin signaling cascade regulates the aggregation of DRG neurons. These findings deepen our understanding of the mechanisms involved in histogenesis and potential disease development, as mechanical signals arising from substrate stiffness play a crucial role in these processes.

Topics: Animals; Rats; Axons; Cell-Matrix Junctions; Ganglia, Spinal; Neurons; Signal Transduction

PubMed: 38048221
DOI: 10.1016/j.celrep.2023.113522

Review

Authors: Katherine M Young, Cynthia A Reinhart-King

The mechanisms by which cells sense their mechanical environment and transduce the signal through focal adhesions and signaling pathways to the nucleus is an area of key focus for the field of mechanobiology. In the past two years, there has been expansion of our knowledge of commonly studied pathways, such as YAP/TAZ, FAK/Src, RhoA/ROCK, and Piezo1 signaling, as well as the discovery of new interactions, such as the effect of matrix rigidity of cell mitochondrial function and metabolism, which represent a new and exciting direction for the field as a whole. This review covers the most recent advances in the field of substrate stiffness sensing as well as perspective on future directions.

Topics: Adaptor Proteins, Signal Transducing; YAP-Signaling Proteins; Signal Transduction; Focal Adhesions; Mechanotransduction, Cellular

PubMed: 37473514
DOI: 10.1016/j.ceb.2023.102208

Review

Authors: Jurjan Aman, Coert Margadant

The endothelium is a dynamic, semipermeable layer lining all blood vessels, regulating blood vessel formation and barrier function. Proper composition and function of the endothelial barrier are required for fluid homeostasis, and clinical conditions characterized by barrier disruption are associated with severe morbidity and high mortality rates. Endothelial barrier properties are regulated by cell-cell junctions and intracellular signaling pathways governing the cytoskeleton, but recent insights indicate an increasingly important role for integrin-mediated cell-matrix adhesion and signaling in endothelial barrier regulation. Here, we discuss diseases characterized by endothelial barrier disruption, and provide an overview of the composition of endothelial cell-matrix adhesion complexes and associated signaling pathways, their crosstalk with cell-cell junctions, and with other receptors. We further present recent insights into the role of cell-matrix adhesions in the developing and mature/adult endothelium of various vascular beds, and discuss how the dynamic regulation and turnover of cell-matrix adhesions regulates endothelial barrier function in (patho)physiological conditions like angiogenesis, inflammation and in response to hemodynamic stress. Finally, as clinical conditions associated with vascular leak still lack direct treatment, we focus on how understanding of endothelial cell-matrix adhesion may provide novel targets for treatment, and discuss current translational challenges and future perspectives.

Topics: Integrins; Endothelial Cells; Intercellular Junctions; Cell-Matrix Junctions; Endothelium, Vascular; Cell Adhesion

PubMed: 36730379
DOI: 10.1161/CIRCRESAHA.122.322332

Review

Authors: Jennifer L Bays, Kris A DeMali

Vinculin was identified as a component of focal adhesions and adherens junctions nearly 40 years ago. Since that time, remarkable progress has been made in understanding its activation, regulation and function. Here we discuss the current understanding of the roles of vinculin in cell-cell and cell-matrix adhesions. Emphasis is placed on the how vinculin is recruited, activated and regulated. We also highlight the recent understanding of how vinculin responds to and transmits force at integrin- and cadherin-containing adhesion complexes to the cytoskeleton. Furthermore, we discuss roles of vinculin in binding to and rearranging the actin cytoskeleton.

Topics: Actin Cytoskeleton; Adherens Junctions; Animals; Cadherins; Cell Adhesion; Cell Movement; Focal Adhesions; Humans; Integrins; Mechanotransduction, Cellular; Models, Molecular; Protein Interaction Maps; Vinculin

PubMed: 28401269
DOI: 10.1007/s00018-017-2511-3

Review

Authors: J C Adams

Cell-extracellular matrix contacts are points on cell surfaces where adhesion receptors tether cells to matrix and are linked intracellularly to cytoskeletal components. These structures integrate cell organisation within tissues, support cell motility and specialised activities of differentiated cells, and transduce extracellular signals. Current characterisations of matrix contacts are based on morphological and biochemical criteria, yet the levels of definition of different contact types are very varied. Some contacts are surprisingly little-studied given their likely importance in vivo. Here, I describe the general features of matrix contacts, review the functions and molecular composition of major types of transient and stable matrix contacts, and discuss the information that is emerging on contact integration and dynamics in single cells.

Topics: Animals; Cell-Matrix Junctions; Extracellular Matrix; Humans

PubMed: 11315186
DOI: 10.1007/PL00000864

Review

Authors: Stephen P Evanko, Markku I Tammi, Raija H Tammi...

Hyaluronan is a multifunctional glycosaminoglycan that forms the structural basis of the pericellular matrix. Hyaluronan is extruded directly through the plasma membrane by one of three hyaluronan synthases and anchored to the cell surface by the synthase or cell surface receptors such as CD44 or RHAMM. Aggregating proteoglycans and other hyaluronan-binding proteins, contribute to the material and biological properties of the matrix and regulate cell and tissue function. The pericellular matrix plays multiple complex roles in cell adhesion/de-adhesion, and cell shape changes associated with proliferation and locomotion. Time-lapse studies show that pericellular matrix formation facilitates cell detachment and mitotic cell rounding. Hyaluronan crosslinking occurs through various proteins, such as tenascin, TSG-6, inter-alpha-trypsin inhibitor, pentraxin and TSP-1. This creates higher order levels of structured hyaluronan that may regulate inflammation and other biological processes. Microvillous or filopodial membrane protrusions are created by active hyaluronan synthesis, and form the scaffold of hyaluronan coats in certain cells. The importance of the pericellular matrix in cellular mechanotransduction and the response to mechanical strain are also discussed.

Topics: Animals; Cell Adhesion; Cell Membrane; Cell Movement; Cell Proliferation; Cell-Matrix Junctions; Cross-Linking Reagents; Extracellular Matrix; Humans; Hyaluronic Acid; Signal Transduction

PubMed: 17804111
DOI: 10.1016/j.addr.2007.08.008