Gijsje Koenderink | Delft University of Technology (original) (raw)

Papers by Gijsje Koenderink

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

Frontiers in Oncology

Cholangiocarcinoma (CCA) is a type of liver cancer with an aggressive phenotype and dismal outcom... more Cholangiocarcinoma (CCA) is a type of liver cancer with an aggressive phenotype and dismal outcome in patients. The metastasis of CCA cancer cells to distant organs, commonly lung and lymph nodes, drastically reduces overall survival. However, mechanistic insight how CCA invades these metastatic sites is still lacking. This is partly because currently available models fail to mimic the complexity of tissue-specific environments for metastatic CCA. To create an in vitro model in which interactions between epithelial tumor cells and their surrounding extracellular matrix (ECM) can be studied in a metastatic setting, we combined patient-derived CCA organoids (CCAOs) (n=3) with decellularized human lung (n=3) and decellularized human lymph node (n=13). Decellularization resulted in removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin. Proteomic analyses showed a tissue-specific ECM protein signature reflecting tissue functioning as...

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

Frontiers in Cell and Developmental Biology

The mammalian cytoskeleton forms a mechanical continuum that spans across the cell, connecting th... more The mammalian cytoskeleton forms a mechanical continuum that spans across the cell, connecting the cell surface to the nucleus via transmembrane protein complexes in the plasma and nuclear membranes. It transmits extracellular forces to the cell interior, providing mechanical cues that influence cellular decisions, but also actively generates intracellular forces, enabling the cell to probe and remodel its tissue microenvironment. Cells adapt their gene expression profile and morphology to external cues provided by the matrix and adjacent cells as well as to cell-intrinsic changes in cytoplasmic and nuclear volume. The cytoskeleton is a complex filamentous network of three interpenetrating structural proteins: actin, microtubules, and intermediate filaments. Traditionally the actin cytoskeleton is considered the main contributor to mechanosensitivity. This view is now shifting owing to the mounting evidence that the three cytoskeletal filaments have interdependent functions due to c...

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, 2022

Hyaluronic acid is an abundant polyelectrolyte in the human body that forms extracellular hydroge... more Hyaluronic acid is an abundant polyelectrolyte in the human body that forms extracellular hydrogels in connective tissues. It is essential for regulating tissue biomechanics and cell-cell communication, yet hyaluronan overexpression is associated with pathological situations such as cancer and multiple sclerosis. Due to its enormous molecular weight (in the range of millions of Daltons), accumulation of hyaluronan hinders transport of macromolecules including nutrients and growth factors through tissues and also hampers drug delivery. However, the exact contribution of hyaluronan to tissue penetrability is poorly understood due to the complex structure and molecular composition of tissues. Here we reconstitute biomimetic hyaluronan gels and systematically investigate the effects of gel composition and crosslinking on the diffusion of microscopic tracer particles. We combine ensemble-averaged measurements via differential dynamic microscopy with single-particle tracking. We show that...

Abstract: The mitochondrion is vital for many metabolic pathways in the cell, contributing all or... more Abstract: The mitochondrion is vital for many metabolic pathways in the cell, contributing all or important constituent enzymes for diverse functions such as β-oxidation of fatty acids, the urea cycle, the citric acid cycle, and ATP synthesis. The mitochondrion is also a major site of reactive oxygen species (ROS) production in the cell. Aberrant production of mitochondrial ROS can have dramatic effects on cellular function, in part, due to oxidative modification of key metabolic proteins localized in the mitochondrion. The cell is equipped with myriad antioxidant enzyme systems to combat deleterious ROS production in mitochondria, with the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) acting as the chief ROS scavenging enzyme in the cell. Factors that affect the expression and/or the activity of MnSOD, resulting in diminished antioxidant capacity of the cell, can have extraordinary consequences on the overall health of the cell by altering mitochondrial me...

arXiv: Biological Physics, 2019

Collagen forms the structural scaffold of connective tissues in all mammals. Tissues are remarkab... more Collagen forms the structural scaffold of connective tissues in all mammals. Tissues are remarkably resistant against mechanical deformations because collagen molecules hierarchically self-assemble in fibrous networks that stiffen with increasing strain. Nevertheless, collagen networks do fracture when tissues are overloaded or subject to pathological conditions such as aneurysms. Prior studies of the role of collagen in tissue fracture have mainly focused on tendons, which contain highly aligned bundles of collagen. By contrast, little is known about fracture of the orientationally more disordered collagen networks present in many other tissues such as skin and cartilage. Here, we combine shear rheology of reconstituted collagen networks with computer simulations to investigate the primary determinants of fracture in disordered collagen networks. We show that the fracture strain is controlled by the coordination number of the network junctions, with less connected networks fracturi...

The actin and microtubule cytoskeletons form active networks in the cell that can contract and re... more The actin and microtubule cytoskeletons form active networks in the cell that can contract and remodel, resulting in vital cellular processes as cell division and motility. Motor proteins play an important role in generating the forces required for these processes, but more recently the concept of passive cross-linkers being able to generate forces has emerged. So far, these passive cross-linkers have been studied in the context of separate actin and microtubule systems. Here, we show that crosslinkers also allow actin and microtubules to exert forces on each other. More specifically, we study single actin filaments that are cross-linked to growing microtubule ends, using in vitro reconstitution, computer simulations, and a minimal theoretical model. We show that microtubules can transport actin filaments over large (micrometer-range) distances, and find that this transport results from two antagonistic forces arising from the binding of cross-linkers to the overlap between the acti...

International Journal of Molecular Sciences, 2020

Subjects with diabetes mellitus (DM) have an increased risk of arterial thrombosis, to which chan... more Subjects with diabetes mellitus (DM) have an increased risk of arterial thrombosis, to which changes in clot structure and mechanics may contribute. Another contributing factor might be an increased formation of neutrophil extracellular traps (NETs) in DM. NETs are mainly formed during the acute phase of disease and form a network within the fibrin matrix, thereby influencing clot properties. Previous research has shown separate effects of NETs and DM on clot properties, therefore our aim was to study how DM affects clot properties in a model resembling an acute phase of disease with NETs formation. Clots were prepared from citrated plasma from subjects with and without DM with the addition of NETs, induced in neutrophils by S. aureus bacteria or phorbol myristate acetate (PMA). Structural parameters were measured using scanning electron microscopy, mechanical properties using rheology, and sensitivity to lysis using a fluorescence-based fibrinolysis assay. Plasma clots from subject...

Many biopolymer hydrogels are environmentally responsive because they are held together by physic... more Many biopolymer hydrogels are environmentally responsive because they are held together by physical associations that depend on pH and temperature. Here we investigate how the pH and temperature response of the rheology of hyaluronan hydrogels is connected to the underlying molecular interactions. Hyaluronan is an essential structural biopolymer in the human body with many applications in biomedicine. Using two-dimensional infrared (2DIR) spectroscopy, we show that hyaluronan chains become connected by hydrogen bonds when the pH is changed from 7.0 to 2.5, and that the bond density at pH 2.5 is independent of temperature. Temperature-dependent rheology measurements show that due to this hydrogen bonding the stress relaxation at pH 2.5 is strongly slowed down in comparison to pH 7.0, consistent with the sticky reptation model of associative polymers. From the flow activation energy we conclude that each polymer is crosslinked by multiple (5-15) hydrogen bonds to others, causing slow ...

Soft Matter, 2020

We show that the diffusivity of particles in biomimetic extracellular hydrogels based on hyaluron... more We show that the diffusivity of particles in biomimetic extracellular hydrogels based on hyaluronan depends on the stress relaxation dynamics of the hydrogel and is strongly affected by the presence of collagen fibers.

ABSTRACTFilamentous proteins are responsible for the superior mechanical strength of our cells an... more ABSTRACTFilamentous proteins are responsible for the superior mechanical strength of our cells and tissues. The remarkable mechanical properties of protein filaments are tied to their complex molecular packing structure. However, since these filaments have widths of several to tens of nanometers, it has remained challenging to quantitatively probe their molecular mass density and three-dimensional packing order. Scanning transmission electron microscopy (STEM) is a powerful tool to perform simultaneous mass and morphology measurements on filamentous proteins at high resolution, but its applicability has been greatly limited by the lack of automated image processing methods. Here, we demonstrate a semi-automated tracking algorithm that is capable of analyzing the molecular packing density of intra- and extracellular protein filaments over a broad mass range from STEM images. We prove the wide applicability of the technique by analyzing the mass densities of two cytoskeletal proteins ...

Microtubule-dependent organization of membrane organelles, such as the endoplasmic reticulum, occ... more Microtubule-dependent organization of membrane organelles, such as the endoplasmic reticulum, occurs through motor-based pulling and by coupling polymer dynamics to membrane remodeling. Membrane binding to dynamic microtubule ends involves transient interactions, but how such interactions can lead to membrane deformation is unclear. Here, we reconstitute membrane tubulation in a minimal system with giant unilamellar vesicles, dynamic microtubules, End-Binding (EB) proteins and a membrane-targeted polypeptide that interacts with EBs and microtubules. We demonstrate that these components are sufficient to induce not only membrane tubulation by growing microtubule ends, but also motor-independent membrane sliding along microtubule shafts and tube pulling by shrinking microtubules. Experiments and modeling reveal that the first two mechanisms can be explained by adhesion-driven biased membrane spreading on microtubules. Attachments to growing and shrinking microtubule ends can sustain f...

Soft Matter, 2018

Glycosaminoglycan-based microgels are of interest for biomedical applications because of their ab... more Glycosaminoglycan-based microgels are of interest for biomedical applications because of their ability to retain and gradually release bioactive cationic proteins.

Biophysical Journal, 2017

Mechanosensitive ion channels are gated open and shut by changes in membrane tension enabling the... more Mechanosensitive ion channels are gated open and shut by changes in membrane tension enabling the conversion of mechanical stimuli into changes in ionic composition and electrical signalling. However, the precise structural and biophysical mechanisms underlying these processes remain unclear. TREK-2 is a eukaryotic mechanosensitive ion channel that belongs to the Two-Pore Domain (K2P) family of Kþ channels and is widely expressed in both the central and peripheral nervous system. I will discuss our recent structural, functional and computational studies which examine how TREK-2 responds to stretch-induced changes in the large lateral forces that vary with depth across the bilayer, and in particular how the asymmetric structure of the channel contributes to this process.

Current opinion in cell biology, 2015

Cell shape and mechanics are determined by the interplay of three distinct cytoskeletal networks,... more Cell shape and mechanics are determined by the interplay of three distinct cytoskeletal networks, made of actin filaments, microtubules, and intermediate filaments. These three types of cytoskeletal polymers have rather different structural and physical properties, enabling specific cellular functions. However, there is growing evidence that the three cytoskeletal subsystems also exhibit strongly coupled functions necessary for polarization, cell migration, and mechano-responsiveness. Here we summarize this evidence from a biophysical point of view, focusing on physical (direct) interactions between the cytoskeletal elements and their influence on cell mechanics and cell migration.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

Frontiers in Oncology

Cholangiocarcinoma (CCA) is a type of liver cancer with an aggressive phenotype and dismal outcom... more Cholangiocarcinoma (CCA) is a type of liver cancer with an aggressive phenotype and dismal outcome in patients. The metastasis of CCA cancer cells to distant organs, commonly lung and lymph nodes, drastically reduces overall survival. However, mechanistic insight how CCA invades these metastatic sites is still lacking. This is partly because currently available models fail to mimic the complexity of tissue-specific environments for metastatic CCA. To create an in vitro model in which interactions between epithelial tumor cells and their surrounding extracellular matrix (ECM) can be studied in a metastatic setting, we combined patient-derived CCA organoids (CCAOs) (n=3) with decellularized human lung (n=3) and decellularized human lymph node (n=13). Decellularization resulted in removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin. Proteomic analyses showed a tissue-specific ECM protein signature reflecting tissue functioning as...

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

Frontiers in Cell and Developmental Biology

The mammalian cytoskeleton forms a mechanical continuum that spans across the cell, connecting th... more The mammalian cytoskeleton forms a mechanical continuum that spans across the cell, connecting the cell surface to the nucleus via transmembrane protein complexes in the plasma and nuclear membranes. It transmits extracellular forces to the cell interior, providing mechanical cues that influence cellular decisions, but also actively generates intracellular forces, enabling the cell to probe and remodel its tissue microenvironment. Cells adapt their gene expression profile and morphology to external cues provided by the matrix and adjacent cells as well as to cell-intrinsic changes in cytoplasmic and nuclear volume. The cytoskeleton is a complex filamentous network of three interpenetrating structural proteins: actin, microtubules, and intermediate filaments. Traditionally the actin cytoskeleton is considered the main contributor to mechanosensitivity. This view is now shifting owing to the mounting evidence that the three cytoskeletal filaments have interdependent functions due to c...

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, 2022

Hyaluronic acid is an abundant polyelectrolyte in the human body that forms extracellular hydroge... more Hyaluronic acid is an abundant polyelectrolyte in the human body that forms extracellular hydrogels in connective tissues. It is essential for regulating tissue biomechanics and cell-cell communication, yet hyaluronan overexpression is associated with pathological situations such as cancer and multiple sclerosis. Due to its enormous molecular weight (in the range of millions of Daltons), accumulation of hyaluronan hinders transport of macromolecules including nutrients and growth factors through tissues and also hampers drug delivery. However, the exact contribution of hyaluronan to tissue penetrability is poorly understood due to the complex structure and molecular composition of tissues. Here we reconstitute biomimetic hyaluronan gels and systematically investigate the effects of gel composition and crosslinking on the diffusion of microscopic tracer particles. We combine ensemble-averaged measurements via differential dynamic microscopy with single-particle tracking. We show that...

Abstract: The mitochondrion is vital for many metabolic pathways in the cell, contributing all or... more Abstract: The mitochondrion is vital for many metabolic pathways in the cell, contributing all or important constituent enzymes for diverse functions such as β-oxidation of fatty acids, the urea cycle, the citric acid cycle, and ATP synthesis. The mitochondrion is also a major site of reactive oxygen species (ROS) production in the cell. Aberrant production of mitochondrial ROS can have dramatic effects on cellular function, in part, due to oxidative modification of key metabolic proteins localized in the mitochondrion. The cell is equipped with myriad antioxidant enzyme systems to combat deleterious ROS production in mitochondria, with the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) acting as the chief ROS scavenging enzyme in the cell. Factors that affect the expression and/or the activity of MnSOD, resulting in diminished antioxidant capacity of the cell, can have extraordinary consequences on the overall health of the cell by altering mitochondrial me...

arXiv: Biological Physics, 2019

Collagen forms the structural scaffold of connective tissues in all mammals. Tissues are remarkab... more Collagen forms the structural scaffold of connective tissues in all mammals. Tissues are remarkably resistant against mechanical deformations because collagen molecules hierarchically self-assemble in fibrous networks that stiffen with increasing strain. Nevertheless, collagen networks do fracture when tissues are overloaded or subject to pathological conditions such as aneurysms. Prior studies of the role of collagen in tissue fracture have mainly focused on tendons, which contain highly aligned bundles of collagen. By contrast, little is known about fracture of the orientationally more disordered collagen networks present in many other tissues such as skin and cartilage. Here, we combine shear rheology of reconstituted collagen networks with computer simulations to investigate the primary determinants of fracture in disordered collagen networks. We show that the fracture strain is controlled by the coordination number of the network junctions, with less connected networks fracturi...

The actin and microtubule cytoskeletons form active networks in the cell that can contract and re... more The actin and microtubule cytoskeletons form active networks in the cell that can contract and remodel, resulting in vital cellular processes as cell division and motility. Motor proteins play an important role in generating the forces required for these processes, but more recently the concept of passive cross-linkers being able to generate forces has emerged. So far, these passive cross-linkers have been studied in the context of separate actin and microtubule systems. Here, we show that crosslinkers also allow actin and microtubules to exert forces on each other. More specifically, we study single actin filaments that are cross-linked to growing microtubule ends, using in vitro reconstitution, computer simulations, and a minimal theoretical model. We show that microtubules can transport actin filaments over large (micrometer-range) distances, and find that this transport results from two antagonistic forces arising from the binding of cross-linkers to the overlap between the acti...

International Journal of Molecular Sciences, 2020

Subjects with diabetes mellitus (DM) have an increased risk of arterial thrombosis, to which chan... more Subjects with diabetes mellitus (DM) have an increased risk of arterial thrombosis, to which changes in clot structure and mechanics may contribute. Another contributing factor might be an increased formation of neutrophil extracellular traps (NETs) in DM. NETs are mainly formed during the acute phase of disease and form a network within the fibrin matrix, thereby influencing clot properties. Previous research has shown separate effects of NETs and DM on clot properties, therefore our aim was to study how DM affects clot properties in a model resembling an acute phase of disease with NETs formation. Clots were prepared from citrated plasma from subjects with and without DM with the addition of NETs, induced in neutrophils by S. aureus bacteria or phorbol myristate acetate (PMA). Structural parameters were measured using scanning electron microscopy, mechanical properties using rheology, and sensitivity to lysis using a fluorescence-based fibrinolysis assay. Plasma clots from subject...

Many biopolymer hydrogels are environmentally responsive because they are held together by physic... more Many biopolymer hydrogels are environmentally responsive because they are held together by physical associations that depend on pH and temperature. Here we investigate how the pH and temperature response of the rheology of hyaluronan hydrogels is connected to the underlying molecular interactions. Hyaluronan is an essential structural biopolymer in the human body with many applications in biomedicine. Using two-dimensional infrared (2DIR) spectroscopy, we show that hyaluronan chains become connected by hydrogen bonds when the pH is changed from 7.0 to 2.5, and that the bond density at pH 2.5 is independent of temperature. Temperature-dependent rheology measurements show that due to this hydrogen bonding the stress relaxation at pH 2.5 is strongly slowed down in comparison to pH 7.0, consistent with the sticky reptation model of associative polymers. From the flow activation energy we conclude that each polymer is crosslinked by multiple (5-15) hydrogen bonds to others, causing slow ...

Soft Matter, 2020

We show that the diffusivity of particles in biomimetic extracellular hydrogels based on hyaluron... more We show that the diffusivity of particles in biomimetic extracellular hydrogels based on hyaluronan depends on the stress relaxation dynamics of the hydrogel and is strongly affected by the presence of collagen fibers.

ABSTRACTFilamentous proteins are responsible for the superior mechanical strength of our cells an... more ABSTRACTFilamentous proteins are responsible for the superior mechanical strength of our cells and tissues. The remarkable mechanical properties of protein filaments are tied to their complex molecular packing structure. However, since these filaments have widths of several to tens of nanometers, it has remained challenging to quantitatively probe their molecular mass density and three-dimensional packing order. Scanning transmission electron microscopy (STEM) is a powerful tool to perform simultaneous mass and morphology measurements on filamentous proteins at high resolution, but its applicability has been greatly limited by the lack of automated image processing methods. Here, we demonstrate a semi-automated tracking algorithm that is capable of analyzing the molecular packing density of intra- and extracellular protein filaments over a broad mass range from STEM images. We prove the wide applicability of the technique by analyzing the mass densities of two cytoskeletal proteins ...

Microtubule-dependent organization of membrane organelles, such as the endoplasmic reticulum, occ... more Microtubule-dependent organization of membrane organelles, such as the endoplasmic reticulum, occurs through motor-based pulling and by coupling polymer dynamics to membrane remodeling. Membrane binding to dynamic microtubule ends involves transient interactions, but how such interactions can lead to membrane deformation is unclear. Here, we reconstitute membrane tubulation in a minimal system with giant unilamellar vesicles, dynamic microtubules, End-Binding (EB) proteins and a membrane-targeted polypeptide that interacts with EBs and microtubules. We demonstrate that these components are sufficient to induce not only membrane tubulation by growing microtubule ends, but also motor-independent membrane sliding along microtubule shafts and tube pulling by shrinking microtubules. Experiments and modeling reveal that the first two mechanisms can be explained by adhesion-driven biased membrane spreading on microtubules. Attachments to growing and shrinking microtubule ends can sustain f...

Soft Matter, 2018

Glycosaminoglycan-based microgels are of interest for biomedical applications because of their ab... more Glycosaminoglycan-based microgels are of interest for biomedical applications because of their ability to retain and gradually release bioactive cationic proteins.

Biophysical Journal, 2017

Mechanosensitive ion channels are gated open and shut by changes in membrane tension enabling the... more Mechanosensitive ion channels are gated open and shut by changes in membrane tension enabling the conversion of mechanical stimuli into changes in ionic composition and electrical signalling. However, the precise structural and biophysical mechanisms underlying these processes remain unclear. TREK-2 is a eukaryotic mechanosensitive ion channel that belongs to the Two-Pore Domain (K2P) family of Kþ channels and is widely expressed in both the central and peripheral nervous system. I will discuss our recent structural, functional and computational studies which examine how TREK-2 responds to stretch-induced changes in the large lateral forces that vary with depth across the bilayer, and in particular how the asymmetric structure of the channel contributes to this process.

Current opinion in cell biology, 2015

Cell shape and mechanics are determined by the interplay of three distinct cytoskeletal networks,... more Cell shape and mechanics are determined by the interplay of three distinct cytoskeletal networks, made of actin filaments, microtubules, and intermediate filaments. These three types of cytoskeletal polymers have rather different structural and physical properties, enabling specific cellular functions. However, there is growing evidence that the three cytoskeletal subsystems also exhibit strongly coupled functions necessary for polarization, cell migration, and mechano-responsiveness. Here we summarize this evidence from a biophysical point of view, focusing on physical (direct) interactions between the cytoskeletal elements and their influence on cell mechanics and cell migration.