Microfluidic modeling of cell-cell interactions in malaria pathogenesis.
Ontology highlight
ABSTRACT:
SUBMITTER: Antia M
PROVIDER: S-EPMC1924869 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Current in vitro models of the leukocyte adhesion cascade cannot be used for real-time studies of the entire leukocyte adhesion cascade, including rolling, adhesion, and migration in a single assay. In this study, we have developed and validated a novel bioinspired microfluidic assay (bMFA) and used it to test the hypothesis that blocking of specific steps in the adhesion/migration cascade significantly affects other steps of the cascade. The bMFA consists of an endothelialized microvascular network in communication with a tissue compartment via a 3 ?m porous barrier. Human neutrophils in bMFA preferentially adhered to activated human endothelial cells near bifurcations with rolling and adhesion patterns in close agreement with in vivo observations. Treating endothelial cells with monoclonal antibodies to E-selectin or ICAM-1 or treating neutrophils with wortmannin reduced rolling, adhesion, and migration of neutrophils to 60%, 20%, and 18% of their respective control values. Antibody blocking of specific steps in the adhesion/migration cascade (e.g., mAb to E-selectin) significantly downregulated other steps of the cascade (e.g., migration). This novel in vitro assay provides a realistic human cell based model for basic science studies, identification of new treatment targets, selection of pathways to target validation, and rapid screening of candidate agents.
| S-EPMC4139165 | biostudies-literature
Project description:Microfluidics have been used to create "body-on-chip" systems to mimic in vivo cellular interactions with a high level of control. Most such systems rely on optical observation of cells as a readout. In this work we integrated a cell-cell interaction chip with online microchip electrophoresis immunoassay to monitor the effects of the interaction on protein secretion dynamics. The system was used to investigate the effects of adipocytes on insulin secretion. Chips were loaded with 190 000 3T3-L1 adipocytes and a single islet of Langerhans in separate chambers. The chambers were perfused at 300-600 nL/min so that adipocyte secretions flowed over the islets for 3 h. Adipocytes produced 80 μM of nonesterified fatty acids (NEFAs), a factor known to impact insulin secretion, at the islets. After perfusion, islets were challenged with a step change in glucose from 3 to 11 mM while monitoring insulin secretion at 8 s intervals by online immunoassay. Adipocyte treatment augmented insulin secretion by 6-fold compared to controls. The effect was far greater than comparable concentrations of NEFA applied to the islets demonstrating that adipocytes release multiple factors that can strongly potentiate insulin secretion. The experiments reveal that integration of chemical analysis with cell-cell interaction can provide valuable insights into cellular functions.
| S-EPMC6943824 | biostudies-literature
Project description:Invasion of the extracellular matrix is a critical step in the colonization of metastatic tumors. The invasion process is thought to be driven by both chemokine signaling and interactions between invading cancer cells and physical components of the metastatic niche, including endothelial cells that line capillary walls and serve as a barrier to both diffusion and invasion of the underlying tissue. Transwell chambers, a tool for generating artificial chemokine gradients to induce cell migration, have facilitated recent work to investigate the chemokine contributions to matrix invasion. These chambers, however, are poorly designed for imaging, which limits their use in investigating the physical cell-cell and cell-matrix interactions driving matrix invasion. Microfluidic devices offer a promising model in which the invasion process can be imaged. Many current designs, however, have limited surface areas and possess intricate geometries that preclude the use of standard staining protocols to visualize cells and matrix proteins. In this work, we present a novel microfluidic platform for imaging cell-cell and cell-matrix interactions driving metastatic cancer cell matrix invasion. Our model is applied to investigate how endothelial cell-secreted matrix proteins and the physical endothelial monolayer itself interact with invading metastatic breast cancer cells to facilitate invasion of an underlying type I collagen gel. The results show that matrix invasion of metastatic breast cancer cells is significantly enhanced in the presence of live endothelial cells. Probing this interaction further, our platform revealed that, while the fibronectin-rich matrix deposited by endothelial cells was not sufficient to drive invasion alone, metastatic breast cancer cells were able to exploit components of energetically inactivated endothelial cells to gain entry into the underlying matrix. These findings reveal novel cell-cell interactions driving a key step in the colonization of metastatic tumors and have important implications for designing drugs targeted at preventing cancer metastasis.
| S-EPMC5749210 | biostudies-literature
Project description:The anti-tumor activity of the immune system is increasingly recognized as critical for the mounting of a prolonged and effective response to cancer growth and invasion, and for preventing recurrence following resection or treatment. As the knowledge of tumor-immune cell interactions has advanced, experimental investigation has been complemented by mathematical modeling with the goal to quantify and predict these interactions. This succinct review offers an overview of recent tumor-immune continuum modeling approaches, highlighting spatial models. The focus is on work published in the past decade, incorporating one or more immune cell types and evaluating immune cell effects on tumor progression. Due to their relevance to cancer, the following immune cells and their combinations are described: macrophages, Cytotoxic T Lymphocytes, Natural Killer cells, dendritic cells, T regulatory cells, and CD4+ T helper cells. Although important insight has been gained from a mathematical modeling perspective, the development of models incorporating patient-specific data remains an important goal yet to be realized for potential clinical benefit.
| S-EPMC6579737 | biostudies-literature
Project description:The importance of the bi-directional natural killer-dendritic cell crosstalk in coordinating anti-tumour and anti-microbial responses in vivo has been well established. However, physical parameters associated with natural killer-dendritic cell interactions have not been fully elucidated. We have previously used a simple "Y" shaped microfluidic device to study natural killer cell-migratory responses toward chemical gradients from a conditioned medium of dendritic cells. There are, however, limitations of the Y-shaped microfluidic devices that could not support higher throughput analyses and studies of cell-cell interactions. Here, we report two novel microfluidic devices (D3-Chip, T2-Chip) we applied in advanced studies of natural killer-cell migrations and their interactions with dendritic cells in vitro. The D3-Chip is an improved version of the previously published Y-shaped device that supports high-throughput analyses and docking of the cells of interest in the migration assay before they are exposed to a chemical gradient. The T2-Chip is created to support analyses of natural killer-dendritic cell cell-cell interactions without the requirement of promoting a natural killer cell to migrate long distances to find a loaded dendritic cell in the device. Using these two microfluidic platforms, we observe quantitative differences in the abilities of the immature and lipopolysaccharide-activated mature dendritic cells to interact with activated natural killer cells. The contact time between the activated natural killer cells and immature dendritic cells is significantly longer than that of the mature dendritic cells. There is a significantly higher frequency of an immature dendritic cell coming into contact with multiple natural killer cells and/or making multiple simultaneous contacts with multiple natural killer cells. To contrast, an activated natural killer cell has a significantly higher frequency of coming into contact with the mature dendritic cells than immature dendritic cells. Collectively, these differences in natural killer-dendritic cell interactions may underlie the differential maturation of immature dendritic cells by activated natural killer cells. Further applications of these microfluidic devices in studying natural killer-dendritic cell crosstalk under defined microenvironments shall enrich our understanding of the functional regulations of natural killer cells and dendritic cells in the natural killer-dendritic cell crosstalk.
| S-EPMC6952968 | biostudies-literature
Project description:Classification of human liver cancer into biologically distinct subgroups suggests origin from different hepatic lineage cells. To clarify contribution of lineage stage in liver oncogenesis, we transduced H-Ras and SV40LT into hepatic progenitor cells (HPC), hepatoblasts (HB) and terminally differentiated adult hepatocytes (AH). Regardless of origin, all transformed cell types acquired common cancer stem cell characteristics in vitro and in vivo. However, expression analysis distinguished tumors of different cellular origin underscoring the contribution of lineage/stage-dependent genetic changes in malignant transformation. Notably, AH-derived tumors showed specific enrichment of c-Myc target genes. These data establish that any hepatic lineage cell can be a target for transformation and acquire common cancer stem cell traits via activation of diverse cell type specific pathways. Profiling of individual tumors derived by Ras/SV40 transformation of hepatic progenitor cell (oval cells), hepatoblasts (fetal) and adult hepatocytes
2013-10-01 | E-GEOD-41312 | biostudies-arrayexpress
Project description:Blood vessel formation, during either normal vascular reconstruction or pathogenic tumour formation, relies upon highly organized cell-cell interactions. Isolating the function of any particular component of this cell-cell communication is often difficult, given the vast complexity of communication networks in multicellular systems. One way to address this problem is to analyse cell-cell communication on the most elementary scale--cell pairs. Here, we describe an integrated dielectrophoretic (DEP)-microfluidic device allowing for such analysis. Single cancer and endothelial cells (ECs) and cell pairs were patterned using DEP force and cultured within a minimally stressful microfluidic channel network. Controlling both the initial cell positions and extracellular environment, we investigated cell motility in homo- and heterotypic cell pairs under diverse conditions. We found that secreted collagen IV and soluble vascular endothelial growth factor have considerable guidance effect on ECs at the level of two interacting cells. Cell interaction rules extracted from the experiments of cell pairs were used to mathematically predict branching patterns characteristic of developing multicellular blood vessels. This integrative analysis method can be extended to other systems involving complex multicellular interactions.
| S-EPMC2615303 | biostudies-literature
Project description:Despite significant advancements over the years, there remains an urgent need for low cost diagnostic approaches that allow for rapid, reliable and sensitive detection of malaria parasites in clinical samples. Our previous work has shown that magnetic resonance relaxometry (MRR) is a potentially highly sensitive tool for malaria diagnosis. A key challenge for making MRR based malaria diagnostics suitable for clinical testing is the fact that MRR baseline fluctuation exists between individuals, making it difficult to detect low level parasitemia. To overcome this problem, it is important to establish the MRR baseline of each individual while having the ability to reliably determine any changes that are caused by the infection of malaria parasite. Here we show that an approach that combines the use of microfluidic cell enrichment with a saponin lysis before MRR detection can overcome these challenges and provide the basis for a highly sensitive and reliable diagnostic approach of malaria parasites. Importantly, as little as 0.0005% of ring stage parasites can be detected reliably, making this ideally suited for the detection of malaria parasites in peripheral blood obtained from patients. The approaches used here are envisaged to provide a new malaria diagnosis solution in the near future.
| S-EPMC4469967 | biostudies-other
Project description:Erythrocyte invasion by Plasmodium falciparum merozoites is an essential step for parasite survival and hence the pathogenesis of malaria. Invasion has been studied intensively, but our cellular understanding has been limited by the fact that it occurs very rapidly: invasion is generally complete within 1 min, and shortly thereafter the merozoites, at least in in vitro culture, lose their invasive capacity. The rapid nature of the process, and hence the narrow time window in which measurements can be taken, have limited the tools available to quantitate invasion. Here we employ optical tweezers to study individual invasion events for what we believe is the first time, showing that newly released P. falciparum merozoites, delivered via optical tweezers to a target erythrocyte, retain their ability to invade. Even spent merozoites, which had lost the ability to invade, retain the ability to adhere to erythrocytes, and furthermore can still induce transient local membrane deformations in the erythrocyte membrane. We use this technology to measure the strength of the adhesive force between merozoites and erythrocytes, and to probe the cellular mode of action of known invasion inhibitory treatments. These data add to our understanding of the erythrocyte-merozoite interactions that occur during invasion, and demonstrate the power of optical tweezers technologies in unraveling the blood-stage biology of malaria.
| S-EPMC4142257 | biostudies-literature
Project description:Cancer initiating cells have been documented in multiple myeloma and believed to be a key factor that initiates and drives tumor growth, differentiation,metastasis, and recurrence of the diseases. Although myeloma initiating cells (MICs) are likely to share many properties of normal stem cells, the underlying mechanisms regulating the fate of MICs are largely unknown. Studies designed to explore such communication are urgently needed to enhance our ability to predict the fate decisions of ICs (self-renewal, differentiation, and proliferation). In this study, we developed a novel system to understand the intercellular communication between MICs and their niche by seamlessly integrating experimental data and mathematical model. We first designed dynamic cell culture experiments and collected three types of cells (side population cells, progenitor cells, and mature myeloma cells) under various cultural conditions with flow cytometry. Then we developed a lineage model with ordinary differential equations by considering secreted factors, self-renewal, differentiation, and other biological functions of those cells, to model the cell–cell interactions among the three cell types. Particle swarm optimization was employed to estimate the model parameters by fitting the experimental data to the lineage model. The theoretical results show that the correlation coefficient analysis can reflect the feedback loops among the three cell types, the intercellular feedback signaling can regulate cell population dynamics, and the culture strategies can decide cell growth. This study provides a basic framework of studying cell–cell interactions in regulating MICs fate.
| S-EPMC4104531 | biostudies-literature