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News Article | September 21, 2016
Site: phys.org

Researchers at the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) have identified a role of receptor tyrosine kinases in the regulation of the cellular mechanosensory machinery, which has relevance for understanding the basis of cancerous growth and developmental abnormalities. The work was published in Nano Letters in August 2016.


News Article | January 6, 2016
Site: www.sciencedaily.com

Scientists from the Mechanobiology Institute, Singapore (MBI) at the National University of Singapore have discovered the universal building blocks that cells use to form initial connections with the surrounding environment. These early adhesions have a consistent size of 100 nanometres, are made up of a cluster of around 50 integrin proteins and are the same even when the surrounding surface is hard or soft. Deciphering the universal nature of adhesion formation may reveal how tumour cells sense and migrate on surfaces of different rigidity, which is a hallmark of metastasis, the devastating ability of cancer to spread throughout the body.


News Article | October 31, 2016
Site: www.sciencenewsdaily.org

An international collaboration between scientists from the Mechanobiology Institute at the National University of Singapore and the Institut Jacques Monod and Université Paris Diderot, France, has revealed how epithelial cell extrusion is regulated by cell density. How epithelial cell extrusion is regulated by cell density An international collaboration has revealed how epithelial cell extrusion is regulated by cell density. The study was published in the scientific journal Current Biology on 5 October 2016. Cell extrusion mechanisms: Making sure to expel an unwanted cell An international collaboration of researchers has revealed how epithelial cell extrusion is regulated by cell density, explains a new report.


News Article | August 22, 2016
Site: phys.org

Scientists from the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) have discovered a new mechanism of cell boundary elongation. Elongation and contraction of the cell boundary is essential for directing changes in cell shape, which is required for the correct development of tissues and organs. The study was published in Current Biology on 11 August 2016.


News Article | December 27, 2016
Site: www.sciencenewsdaily.org

Scientists from the Mechanobiology Institute, Singapore (MBI) at the National University of Singapore (NUS) have discovered that cadherin clusters, which are well known for forming junctions between cells, also play a role in stabilising the cell cortex. The study was published in the scientific journal Current Biology on 15 December 2016. Scientists from the Mechanobiology Institute, Singapore (MBI) at the National University of Singapore (NUS) have discovered that cadherin clusters, which are well known for forming junctions ... Scientists have discovered that cadherin clusters, which are well known for forming junctions between cells, also play a role in stabilizing the cell cortex. Scientists from the Mechanobiology Institute, Singapore at the National University of Singapore have discovered that cadherin clusters, which are well known for forming junctions between cells, ...


News Article | December 27, 2016
Site: www.eurekalert.org

Scientists from the Mechanobiology Institute, Singapore (MBI) at the National University of Singapore (NUS) have discovered that cadherin clusters, which are well known for forming junctions between cells, also play a role in stabilising the cell cortex. The study was published in the scientific journal Current Biology on 15 December 2016. Multicellular life depends on the ability of cells to adhere to one another. This takes place through cell-cell junctions, protein complexes that physically connect cells together. At the core of cell-cell junctions is the protein cadherin, which spans across the cell membrane, sticking out of the cell to connect to cadherins on neighbouring cells. Cadherin also attaches to the internal cell cortex, a dense layer of proteins underneath the cell membrane which has two major components: the filament-forming protein actin that provides structural stability, and the motor protein myosin that enables dynamic movement of the cortex depending on the needs of the cell. This physical bridge between cells enables the transmission of both mechanical and biochemical signals across multicellular tissues. However, scientists have observed clusters of cadherin on the cell surface which are not involved in cell-cell junctions. While it has been speculated that these non-junctional and non-adhesive cadherin clusters are being kept in reserve in order to strengthen or create new cell-cell junctions, the actual function of these clusters remained unknown. With their expertise in cell adhesion and developmental biology, Principal Investigator Assistant Professor Ronen Zaidel-Bar and Research Fellow Dr Anup Padmanabhan of MBI used embryos from the nematode C. elegans to probe the function of these non-junctional cadherin clusters. After tagging the worm equivalent of cadherin, a protein named HMR-1, with a fluorescent marker, they were able to follow its location and movement by live imaging. Focusing their investigation on the zygote, the single fertilised egg cell that develops into an embryo, they discovered that HMR-1 formed non-junctional, non-adhesive clusters similar to cadherin. Even though these non-junctional HMR-1 clusters did not form connections outside of the cell, they still remained internally associated with actin filaments of the cell cortex, but not the myosin motor proteins. In fact, the presence of non-junctional HMR-1 clusters prevents cortical accumulation of myosin and decreases the contractile activity of proteins that drive cortical movement. In order to determine whether non-junctional HMR-1 affected cytokinesis - the physical process by which the cell cortex rotates and contracts to divide the cell into two - the scientists genetically altered the level of HMR-1. Reducing the amount of HMR-1 resulted in faster cytokinesis while increasing HMR-1 levels slowed it down, demonstrating that these non-junctional clusters have a key function in regulating movement of the cell cortex. Analysis of cortical dynamics during cell division revealed that HMR-1 clusters attached to the actin filaments effectively provided drag against cytoskeleton movement, by acting as structural anchors lodged in the cell membrane. The importance of this anchoring in maintaining cell integrity became clear following extended observation of embryos with reduced levels of HMR-1, which were vulnerable to cortical splitting, where a segment of cortex tears away from the cell membrane. In essence, the non-junctional HMR-1 clusters can be thought of as cellular staples that help secure the cortex to the cell surface. The friction from the clusters stabilises the cortex and slows down cortical flow, preventing dramatic cortical deformation, while allowing enough cortical movement for fundamental processes like cytokinesis. This new discovery means that scientists must re-evaluate their understanding of cadherin. The importance of non-junctional cadherin in stabilising the cell cortex must now be considered along with the classical function of cadherin in maintaining cell-cell junctions. This fresh perspective may unlock new avenues of investigation regarding the role of cadherin in health and disease.


News Article | February 15, 2017
Site: phys.org

Intracellular adherens junctions are initiated by interactions between extracellular domains of membrane-bound cadherins (shown in blue) on adjacent cells. On the intracellular side, the cadherins are linked to the actin cytoskeleton via a cytoplasmic plaque, which is chiefly constituted by catenin proteins: beta-catenins (yellow) and alpha-catenins (purple). The plaque also contains another prominent protein called vinculin (green) that primarily responds to mechanical and biochemical signals by extending in length, and in doing so, couples the cadherin-catenin complexes to the actin cytoskeleton (red). Credit: National University of Singapore The development of super resolution microscopy has revolutionised how scientists view and understand the inner workings of the cell. Just as advances in satellite camera technology gave rise to highly detailed maps of the world, so too has super-resolution microscopy allowed researchers to build detailed maps of individual cells. Such is the detail, that not only is the location of individual protein-based machines achievable, but these machines can be broken down into their parts, and the position and orientation of these parts, mapped out as well. In the human body, cells rarely function in isolation. Instead they exist as part of multicellular communities that make up tissues and organs. To ensure the tissue functions correctly, individual cells must remain in physical contact with their surrounding cells. When cells are unable to maintain this contact, devastating diseases may arise, cancer being one of the most dreaded examples. Cell-cell adhesion sites are found at specific regions of the cell periphery. Although many of the protein parts that make up these adhesion sites were known, scientists had yet to determine how each part fit together to make the overall machine. This was because the building blocks of these machines were both far too small for traditional light microscopes, and far too diverse for electron microscopes. One of the main protein parts in these machines are the 'cadherin' proteins. The cadherin of one cell extends outside the cell, and interact with cadherin of another cell. On the inside of the cell, cadherin binds to 'adaptor' proteins, which essentially connect the cadherin to a network of protein filaments known as the cytoskeleton. By forging these robust links, cadherin adhesions not only connect neighbouring cells but allow cells to coordinate their movements, maintain tissue integrity, and relay a myriad of signals important for proper tissue functions. With super-resolution microscopy at their disposal, an international research team led by Assistant Professor Pakorn (Tony) Kanchanawong from the Mechanobiology Institute, Singapore (MBI) at the National University of Singapore (NUS) and the Department of Biomedical Engineering at NUS, as well as Dr Cristina Bertocchi, Research Fellow at MBI, has revealed, for the first time, how the cadherin-based cell-cell contacts are organised. At the heart of the study is a 'map' of how the parts are pieced together into a sophisticated nanoscale cell-cell adhesion machine. The study was published online in Nature Cell Biology in December 2016. Here, the researchers 'mapped' the position and orientation of the protein building blocks of cadherin adhesions. They noted a striking degree of compartmentalisation in the organisation of the protein machinery where components were arranged into multiple layers. The cadherin and the cytoskeleton compartments appeared to be separated by an 'interface layer', which contains vinculin, a stretchable protein which has long been implicated in the cell's ability to sense mechanical force. In this case, Dr Bertocchi observed that vinculin could undergo a dramatic shape-shifting transformation, whereby it would switch from a compact shape to a highly elongated form. This elongated form was sufficient to stretch over a distance of 30 nanometres or more, which was the same distance that cadherin was separated from the cytoskeleton. In a nutshell, vinculin could serve as a bridge to link between the cadherin and actin layers. Further investigation of this structure highlighted that the shape of vinculin (stretched or compact) was determined by both mechanical tension and biochemical signal inputs. Therefore, the ability of vinculin to selectively engage with a highly dynamic actin cytoskeleton highlights vinculin's role in fine-tuning the mechanical properties of cell-cell contacts in response to varying inputs from the extracellular environment. The ability to observe, under a microscope, molecular machines such as the cadherin based cell-cell adhesion highlights the power of super resolution microscopy. In this case, the protein parts that make up the cell-cell adhesion have been mapped out, allowing researchers to better understand how cell-cell contacts are formed, maintained, regulated and reinforced to perform vital biological functions. More information: Cristina Bertocchi et al. Nanoscale architecture of cadherin-based cell adhesions, Nature Cell Biology (2016). DOI: 10.1038/ncb3456


News Article | February 15, 2017
Site: www.eurekalert.org

The development of super resolution microscopy has revolutionised how scientists view and understand the inner workings of the cell. Just as advances in satellite camera technology gave rise to highly detailed maps of the world, so too has super-resolution microscopy allowed researchers to build detailed maps of individual cells. Such is the detail, that not only is the location of individual protein-based machines achievable, but these machines can be broken down into their parts, and the position and orientation of these parts, mapped out as well. In the human body, cells rarely function in isolation. Instead they exist as part of multicellular communities that make up tissues and organs. To ensure the tissue functions correctly, individual cells must remain in physical contact with their surrounding cells. When cells are unable to maintain this contact, devastating diseases may arise, cancer being one of the most dreaded examples. Cell-cell adhesion sites are found at specific regions of the cell periphery. Although many of the protein parts that make up these adhesion sites were known, scientists had yet to determine how each part fit together to make the overall machine. This was because the building blocks of these machines were both far too small for traditional light microscopes, and far too diverse for electron microscopes. One of the main protein parts in these machines are the 'cadherin' proteins. The cadherin of one cell extends outside the cell, and interact with cadherin of another cell. On the inside of the cell, cadherin binds to 'adaptor' proteins, which essentially connect the cadherin to a network of protein filaments known as the cytoskeleton. By forging these robust links, cadherin adhesions not only connect neighbouring cells but allow cells to coordinate their movements, maintain tissue integrity, and relay a myriad of signals important for proper tissue functions. With super-resolution microscopy at their disposal, an international research team led by Assistant Professor Pakorn (Tony) Kanchanawong from the Mechanobiology Institute, Singapore (MBI) at the National University of Singapore (NUS) and the Department of Biomedical Engineering at NUS, as well as Dr Cristina Bertocchi, Research Fellow at MBI, has revealed, for the first time, how the cadherin-based cell-cell contacts are organised. At the heart of the study is a 'map' of how the parts are pieced together into a sophisticated nanoscale cell-cell adhesion machine. The study was published online in Nature Cell Biology in December 2016. Here, the researchers 'mapped' the position and orientation of the protein building blocks of cadherin adhesions. They noted a striking degree of compartmentalisation in the organisation of the protein machinery where components were arranged into multiple layers. The cadherin and the cytoskeleton compartments appeared to be separated by an 'interface layer', which contains vinculin, a stretchable protein which has long been implicated in the cell's ability to sense mechanical force. In this case, Dr Bertocchi observed that vinculin could undergo a dramatic shape-shifting transformation, whereby it would switch from a compact shape to a highly elongated form. This elongated form was sufficient to stretch over a distance of 30 nanometres or more, which was the same distance that cadherin was separated from the cytoskeleton. In a nutshell, vinculin could serve as a bridge to link between the cadherin and actin layers. Further investigation of this structure highlighted that the shape of vinculin (stretched or compact) was determined by both mechanical tension and biochemical signal inputs. Therefore, the ability of vinculin to selectively engage with a highly dynamic actin cytoskeleton highlights vinculin's role in fine-tuning the mechanical properties of cell-cell contacts in response to varying inputs from the extracellular environment. The ability to observe, under a microscope, molecular machines such as the cadherin based cell-cell adhesion highlights the power of super resolution microscopy. In this case, the protein parts that make up the cell-cell adhesion have been mapped out, allowing researchers to better understand how cell-cell contacts are formed, maintained, regulated and re


News Article | October 31, 2016
Site: www.eurekalert.org

An international collaboration between scientists from the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) and the Institut Jacques Monod and Université Paris Diderot, France, has revealed how epithelial cell extrusion is regulated by cell density. The study was published in the scientific journal Current Biology on 5 October 2016. The external and internal surfaces of the body are covered by a layer of cells known as epithelial cell sheets. The classic example of an epithelial cell sheet is skin, but epithelial layers also line internal cavities such as blood vessels, the stomach, and the mouth. The primary role of these cell sheets is to provide a protective barrier against physical damage and infection. In order to perform these functions, the integrity of the epithelial cell sheet must be maintained by balancing cell renewal and removal. For example, the layer of cells lining the intestine is renewed every five days. Deteriorating, damaged, or unnecessary cells are targeted for elimination by apoptosis - the process of programmed cell death - allowing them to be eliminated without causing damage to the neighboring healthy cells, as would occur during inflammation. Removal of these apoptotic cells from the epithelial cell sheet to maintain an intact barrier layer takes place by the process of cell extrusion. To date, studies have shown that epithelial cell extrusion occurs via formation of a contractile ring made up of protein based cables and motors in the cells surrounding the cell targeted for extrusion. The contractile ring tightens around the base of the extruding cell, pushing it out of the epithelial sheet and bringing the surrounding cells together. Although this 'purse-string' mechanism of contraction is commonly seen in epithelial cell sheets, many of these observations have been based on the assumption that the epithelial layer is a collection of individual cells. However, in reality, these multi-cellular sheets are highly complex structures, with large variations in cell dynamics and cell density. In order to account for this level of complexity, an interdisciplinary team of biologists, engineers, and biophysicists was assembled by Professor Benoit Ladoux from MBI and Institut Jacques Monod, and Assistant Professor Yusuke Toyama from MBI. The scientists used microfabrication to create circular micro-patterns surfaces that enabled control of the growth and density of epithelial cell sheets. By observing cell extrusion events in cell sheets grown on these patterns, with time-lapse and traction-force microscopy, they discovered that cell density led to two distinct modes of cell extrusion. At a low cell density, the cells in a tissue are dynamic and mobile. As these cells are moving freely, occasionally cell density becomes high in a small patch in the tissue. Cells at this dense region undergo apoptosis, and the cells surrounding the apoptotic cell selected for extrusion collectively crawl towards the targeted cell, and extend large, flat protrusions called lamellipodia underneath it. This action levers the apoptotic cell out of the sheet, causing its extrusion. However, at high density, cells are too tightly packed to move, preventing collective cell migration and lamellipodia-based extrusion. Under these conditions, the cells surrounding the apoptotic cell form a contractile ring, and use purse-string contraction to squeeze out and extrude the cell. This study revealed, for the first time, that two distinct mechanisms exist to expel apoptotic cells from epithelial cell sheets. Selection between cell extrusion mechanisms is defined by cell density - cell crawling and lamellipodia extension is the predominant mechanism at low density, but purse-string contraction is favoured at high density. The existence of these complementary mechanisms could be important for ensuring the removal of unnecessary cells (e.g. apoptotic cells) in different circumstances to maintain the integrity of the epithelial cell sheet.


News Article | October 31, 2016
Site: www.sciencedaily.com

An international collaboration between scientists from the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) and the Institut Jacques Monod and Université Paris Diderot, France, has revealed how epithelial cell extrusion is regulated by cell density. The study was published in the scientific journal Current Biology. The external and internal surfaces of the body are covered by a layer of cells known as epithelial cell sheets. The classic example of an epithelial cell sheet is skin, but epithelial layers also line internal cavities such as blood vessels, the stomach, and the mouth. The primary role of these cell sheets is to provide a protective barrier against physical damage and infection. In order to perform these functions, the integrity of the epithelial cell sheet must be maintained by balancing cell renewal and removal. For example, the layer of cells lining the intestine is renewed every five days. Deteriorating, damaged, or unnecessary cells are targeted for elimination by apoptosis -- the process of programmed cell death -- allowing them to be eliminated without causing damage to the neighboring healthy cells, as would occur during inflammation. Removal of these apoptotic cells from the epithelial cell sheet to maintain an intact barrier layer takes place by the process of cell extrusion. To date, studies have shown that epithelial cell extrusion occurs via formation of a contractile ring made up of protein based cables and motors in the cells surrounding the cell targeted for extrusion. The contractile ring tightens around the base of the extruding cell, pushing it out of the epithelial sheet and bringing the surrounding cells together. Although this 'purse-string' mechanism of contraction is commonly seen in epithelial cell sheets, many of these observations have been based on the assumption that the epithelial layer is a collection of individual cells. However, in reality, these multi-cellular sheets are highly complex structures, with large variations in cell dynamics and cell density. In order to account for this level of complexity, an interdisciplinary team of biologists, engineers, and biophysicists was assembled by Professor Benoit Ladoux from MBI and Institut Jacques Monod, and Assistant Professor Yusuke Toyama from MBI. The scientists used microfabrication to create circular micro-patterns surfaces that enabled control of the growth and density of epithelial cell sheets. By observing cell extrusion events in cell sheets grown on these patterns, with time-lapse and traction-force microscopy, they discovered that cell density led to two distinct modes of cell extrusion. At a low cell density, the cells in a tissue are dynamic and mobile. As these cells are moving freely, occasionally cell density becomes high in a small patch in the tissue. Cells at this dense region undergo apoptosis, and the cells surrounding the apoptotic cell selected for extrusion collectively crawl towards the targeted cell, and extend large, flat protrusions called lamellipodia underneath it. This action levers the apoptotic cell out of the sheet, causing its extrusion. However, at high density, cells are too tightly packed to move, preventing collective cell migration and lamellipodia-based extrusion. Under these conditions, the cells surrounding the apoptotic cell form a contractile ring, and use purse-string contraction to squeeze out and extrude the cell. This study revealed, for the first time, that two distinct mechanisms exist to expel apoptotic cells from epithelial cell sheets. Selection between cell extrusion mechanisms is defined by cell density -- cell crawling and lamellipodia extension is the predominant mechanism at low density, but purse-string contraction is favoured at high density. The existence of these complementary mechanisms could be important for ensuring the removal of unnecessary cells (e.g. apoptotic cells) in different circumstances to maintain the integrity of the epithelial cell sheet.

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