1,753 research outputs found

    Concepts of GPCR-controlled navigation in the immune system

    No full text
    G-protein-coupled receptor (GPCR) signaling is essential for the spatiotemporal control of leukocyte dynamics during immune responses. For efficient navigation through mammalian tissues, most leukocyte types express more than one GPCR on their surface and sense a wide range of chemokines and chemoattractants, leading to basic forms of leukocyte movement (chemokinesis, haptokinesis, chemotaxis, haptotaxis, and chemorepulsion). How leukocytes integrate multiple GPCR signals and make directional decisions in lymphoid and inflamed tissues is still subject of intense research. Many of our concepts on GPCR-controlled leukocyte navigation in the presence of multiple GPCR signals derive from in vitro chemotaxis studies and lower vertebrates. In this review, we refer to these concepts and critically contemplate their relevance for the directional movement of several leukocyte subsets (neutrophils, T cells, and dendritic cells) in the complexity of mouse tissues. We discuss how leukocyte navigation can be regulated at the level of only a single GPCR (surface expression, competitive antagonism, oligomerization, homologous desensitization, and receptor internalization) or multiple GPCRs (synergy, hierarchical and non-hierarchical competition, sequential signaling, heterologous desensitization, and agonist scavenging). In particular, we will highlight recent advances in understanding GPCR-controlled leukocyte navigation by intravital microscopy of immune cells in mice

    Positive feedback amplification in swarming immune cell populations

    Get PDF
    Several immune cell types (neutrophils, eosinophils, T cells, and innate-like lymphocytes) display coordinated migration patterns when a population, formed of individually responding cells, moves through inflamed or infected tissues. “Swarming” refers to the process in which a population of migrating leukocytes switches from random motility to highly directed chemotaxis to form local cell clusters. Positive feedback amplification underlies this behavior and results from intercellular communication in the immune cell population. We here highlight recent findings on neutrophil swarming from mouse models, zebrafish larvae, and in vitro platforms for human cells, which together advanced our understanding of the principles and molecular mechanisms that shape immune cell swarming

    High-throughput simulation studies of angiogenesis : reverse engineering the role of tip cells and pericytes in vascular development

    Get PDF
    Angiogenesis is the process by which new blood vessels develop by splitting of or by sprouting from existing vessels. In sprouting angiogenesis vessels branch out and connect with other sprouts to form a new network. This process involves both the endothelial cells, which make up the inner lining of a vessel, and the perivascular cells, which surround the vessel. The collective behavior of these cells results in the formation of sprouts and eventually vascular networks. The cells involved in angiogenesis differ in shape and behavior, which affects their collective behavior. Furthermore, the cells also affect one another via diffusive and membrane bound signaling molecules. In this thesis we aim to understand how interactions between multiple cell-types exhibiting subtle differences in behavior change the resulting collective angiogenic sprouting. To this end, we developed cell-based, computational models of angiogenesis, based on the cellular Potts model. The inputs of these models are the observed or hypothesized behavior of individual cells and the output is the resulting collective cell behavior: e.g., the formation of angiogenic sprouts or vascular networks. By assigning different behavior to a subset of the cells, these models can be used to study the interplay between cell types exhibiting different behavior.Centrum Wiskunde & Informatica Netherlands Consortium for Systems BiologyUBL - phd migration 201

    Mathematical models for chemotaxis and their applications in self-organisation phenomena

    Get PDF
    Chemotaxis is a fundamental guidance mechanism of cells and organisms, responsible for attracting microbes to food, embryonic cells into developing tissues, immune cells to infection sites, animals towards potential mates, and mathematicians into biology. The Patlak-Keller-Segel (PKS) system forms part of the bedrock of mathematical biology, a go-to-choice for modellers and analysts alike. For the former it is simple yet recapitulates numerous phenomena; the latter are attracted to these rich dynamics. Here I review the adoption of PKS systems when explaining self-organisation processes. I consider their foundation, returning to the initial efforts of Patlak and Keller and Segel, and briefly describe their patterning properties. Applications of PKS systems are considered in their diverse areas, including microbiology, development, immunology, cancer, ecology and crime. In each case a historical perspective is provided on the evidence for chemotactic behaviour, followed by a review of modelling efforts; a compendium of the models is included as an Appendix. Finally, a half-serious/half-tongue-in-cheek model is developed to explain how cliques form in academia. Assumptions in which scholars alter their research line according to available problems leads to clustering of academics and the formation of "hot" research topics.Comment: 35 pages, 8 figures, Submitted to Journal of Theoretical Biolog

    Breast Cancer Cell Invasion into a Three Dimensional Tumor-Stroma Microenvironment

    Get PDF
    abstract: In this study, to model 3D chemotactic tumor-stroma invasion in vitro, we developed an innovative microfluidic chip allowing side-by-side positioning of 3D hydrogel-based matrices. We were able to (1) create a dual matrix architecture that extended in a continuous manner, thus allowing invasion from one 3D matrix to another, and (2) establish distinct regions of tumor and stroma cell/ECM compositions, with a clearly demarcated tumor invasion front, thus allowing us to quantitatively analyze progression of cancer cells into the stroma at a tissue or single-cell level. We showed significantly enhanced cancer cell invasion in response to a transient gradient of epidermal growth factor (EGF). 3D tracking at the single-cell level displayed increased migration speed and persistence. Subsequently, we analyzed changes in expression of EGF receptors, cell aspect ratio, and protrusive activity. These findings show the unique ability of our model to quantitatively analyze 3D chemotactic invasion, both globally by tracking the progression of the invasion front, and at the single-cell level by examining changes in cellular behavior and morphology using high-resolution imaging. Taken together, we have shown a novel model recapitulating 3D tumor-stroma interactions for studies of real-time cell invasion and morphological changes within a single platform.The final version of this article, as published in Scientific Reports, can be viewed online at: https://www.nature.com/articles/srep3409

    Breast Cancer Cell Invasion into a Three Dimensional Tumor-Stroma Microenvironment

    Get PDF
    In this study, to model 3D chemotactic tumor-stroma invasion in vitro, we developed an innovative microfluidic chip allowing side-by-side positioning of 3D hydrogel-based matrices. We were able to (1) create a dual matrix architecture that extended in a continuous manner, thus allowing invasion from one 3D matrix to another, and (2) establish distinct regions of tumor and stroma cell/ECM compositions, with a clearly demarcated tumor invasion front, thus allowing us to quantitatively analyze progression of cancer cells into the stroma at a tissue or single-cell level. We showed significantly enhanced cancer cell invasion in response to a transient gradient of epidermal growth factor (EGF). 3D tracking at the single-cell level displayed increased migration speed and persistence. Subsequently, we analyzed changes in expression of EGF receptors, cell aspect ratio, and protrusive activity. These findings show the unique ability of our model to quantitatively analyze 3D chemotactic invasion, both globally by tracking the progression of the invasion front, and at the single-cell level by examining changes in cellular behavior and morphology using high-resolution imaging. Taken together, we have shown a novel model recapitulating 3D tumor-stroma interactions for studies of real-time cell invasion and morphological changes within a single platform.National Science Foundation (U.S.) (1510700

    Microfluidic Models of Tumor-Stroma Interactions to Study the Interplay of Cancer Cells with their Surrounding Microenvironment

    Get PDF
    abstract: According to the World Health Organization, cancer is one of the leading causes of death around the world. Although early diagnostics using biomarkers and improved treatments with targeted therapy have reduced the rate of cancer related mortalities, there remain many unknowns regarding the contributions of the tumor microenvironment to cancer progression and therapeutic resistance. The tumor microenvironment plays a significant role by manipulating the progression of cancer cells through biochemical and biophysical signals from the surrounding stromal cells along with the extracellular matrix. As such, there is a critical need to understand how the tumor microenvironment influences the molecular mechanisms underlying cancer metastasis to facilitate the discovery of better therapies. This thesis described the development of microfluidic technologies to study the interplay of cancer cells with their surrounding microenvironment. The microfluidic model was used to assess how exposure to chemoattractant, epidermal growth factor (EGF), impacted 3D breast cancer cell invasion and enhanced cell motility speed was noted in the presence of EGF validating physiological cell behavior. Additionally, breast cancer and patient-derived cancer-associated fibroblast (CAF) cells were co-cultured to study cell-cell crosstalk and how it affected cancer invasion. GPNMB was identified as a novel gene of interest and it was shown that CAFs enhanced breast cancer invasion by up-regulating the expression of GPNMB on breast cancer cells resulting in increased migration speed. Lastly, this thesis described the design, biological validation, and use of this microfluidic platform as a new in vitro 3D organotypic model to study mechanisms of glioma stem cell (GSC) invasion in the context of a vascular niche. It was confirmed that CXCL12-CXCR4 signaling is involved in promoting GSC invasion in a 3D vascular microenvironment, while also demonstrating the effectiveness of the microfluidic as a drug screening assay. Taken together, the broader impacts of the microfluidic model developed in this dissertation include, a possible alternative platform to animal testing that is focused on mimicking human physiology, a potential ex vivo platform using patient-derived cells for studying the interplay of cancer cells with its surrounding microenvironment, and development of future therapeutic strategies tailored toward disrupting key molecular pathways involved in regulatory mechanisms of cancer invasion.Dissertation/ThesisMovie D.2Movie D.1Movie D.3Movie D.4Movie D.5Movie D.6Movie D.7Movie D.8Movie D.9Movie D.10Movie D.12Movie D.11Movie D.13Movie D.14Movie D.15Doctoral Dissertation Biomedical Engineering 201
    • 

    corecore