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Cell Jul 2021Many embryonic organs undergo epithelial morphogenesis to form tree-like hierarchical structures. However, it remains unclear what drives the budding and branching of...
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 -
Nature Cell Biology Mar 2019Extracellular matrix (ECM) mechanical cues have powerful effects on cell proliferation, differentiation and death. Here, starting from an unbiased metabolomics approach,...
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 -
Frontiers in Immunology 2019
Topics: Animals; Cell Adhesion; Cell-Matrix Junctions; Humans; Neoplasms
PubMed: 32038639
DOI: 10.3389/fimmu.2019.03126 -
Nature Cell Biology Feb 2022Metastatic breast cancer cells disseminate to organs with a soft microenvironment. Whether and how the mechanical properties of the local tissue influence their response...
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 -
Cellular and Molecular Life Sciences :... Aug 2017Vinculin 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... (Review)
Review
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 -
The International Journal of... 2022The development and homeostasis of vertebrate organisms depend on the "tree of life", in other words, the intricate network of vascular tubes composed of endothelial... (Review)
Review
The development and homeostasis of vertebrate organisms depend on the "tree of life", in other words, the intricate network of vascular tubes composed of endothelial cells attached to the basement membrane and surrounded by perivascular cells. Although many studies have revealed the fundamental role of cytokines, growth factors and Notch signalling in vascular morphogenesis, we still lack sufficient understanding of the molecular mechanisms controlling the various steps of the angiogenic processes. Emerging data highlight that cell adhesions are key players in vascular morphogenesis. In this review, we focus on endothelial cells and we present the current state of knowledge regarding the role of cell-matrix adhesions in developmental and tumour angiogenesis, attained mainly from genetic studies and animal models.
Topics: Animals; Cell-Matrix Junctions; Endothelial Cells; Morphogenesis; Neoplasms; Neovascularization, Physiologic
PubMed: 34881799
DOI: 10.1387/ijdb.210204vk -
Essays in Biochemistry Oct 2019The ability of cells to migrate is a fundamental physiological process involved in embryonic development, tissue homeostasis, immune surveillance and wound healing. In... (Review)
Review
The ability of cells to migrate is a fundamental physiological process involved in embryonic development, tissue homeostasis, immune surveillance and wound healing. In order for cells to migrate, they must interact with their environment using adhesion receptors, such as integrins, and form specialized adhesion complexes that mediate responses to different extracellular cues. In this review, we discuss the role of integrin adhesion complexes (IACs) in cell migration, highlighting the layers of regulation that are involved, including intracellular signalling cascades, mechanosensing and reciprocal feedback to the extracellular environment. We also discuss the role of IACs in extracellular matrix remodeling and how they impact upon cell migration.
Topics: Actins; Animals; Cell Movement; Cell-Matrix Junctions; Extracellular Matrix; Humans; Integrins; Signal Transduction
PubMed: 31444228
DOI: 10.1042/EBC20190012 -
Circulation Research Feb 2023The endothelium is a dynamic, semipermeable layer lining all blood vessels, regulating blood vessel formation and barrier function. Proper composition and function of... (Review)
Review
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 -
MAP4K4 regulates forces at cell-cell and cell-matrix adhesions to promote collective cell migration.Life Science Alliance Sep 2023Collective cell migration is not only important for development and tissue homeostasis but can also promote cancer metastasis. To migrate collectively, cells need to...
Collective cell migration is not only important for development and tissue homeostasis but can also promote cancer metastasis. To migrate collectively, cells need to coordinate cellular extensions and retractions, adhesion sites dynamics, and forces generation and transmission. Nevertheless, the regulatory mechanisms coordinating these processes remain elusive. Using A431 carcinoma cells, we identify the kinase MAP4K4 as a central regulator of collective migration. We show that MAP4K4 inactivation blocks the migration of clusters, whereas its overexpression decreases cluster cohesion. MAP4K4 regulates protrusion and retraction dynamics, remodels the actomyosin cytoskeleton, and controls the stability of both cell-cell and cell-substrate adhesion. MAP4K4 promotes focal adhesion disassembly through the phosphorylation of the actin and plasma membrane crosslinker moesin but disassembles adherens junctions through a moesin-independent mechanism. By analyzing traction and intercellular forces, we found that MAP4K4 loss of function leads to a tensional disequilibrium throughout the cell cluster, increasing the traction forces and the tension loading at the cell-cell adhesions. Together, our results indicate that MAP4K4 activity is a key regulator of biomechanical forces at adhesion sites, promoting collective migration.
Topics: Cell Adhesion; Cell Movement; Cell-Matrix Junctions; Cytoskeleton; Phosphorylation
PubMed: 37369604
DOI: 10.26508/lsa.202302196 -
Current Opinion in Cell Biology Oct 2016Microbial biofilms and most eukaryotic tissues consist of cells embedded in a three-dimensional extracellular matrix. This matrix serves as a scaffold for cell adhesion... (Review)
Review
Microbial biofilms and most eukaryotic tissues consist of cells embedded in a three-dimensional extracellular matrix. This matrix serves as a scaffold for cell adhesion and a dynamic milieu that provides varying chemical and physical signals to the cells. Besides a vast array of specific molecular components, an extracellular matrix can provide locally heterogeneous microenvironments differing in porosity/diffusion, stiffness, pH, oxygen and metabolites or nutrient levels. Mechanisms of matrix formation, mechanosensing, matrix remodeling, and modulation of cell-cell or cell-matrix interactions and dispersal are being revealed. This perspective article aims to identify such concepts from the fields of biofilm or eukaryotic matrix biology relevant to the other field to help stimulate new questions, approaches, and insights.
Topics: Animals; Bacteria; Biofilms; Cell Communication; Cell-Matrix Junctions; Cellular Microenvironment; Extracellular Matrix; Humans
PubMed: 27257751
DOI: 10.1016/j.ceb.2016.05.005