Thi Phuong Oanh Nguyen

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Nguyen

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Thi Phuong Oanh

ORCID

0000-0003-0192-2456

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Publications 1 - 10 of 10

A versatile gut-on-chip platform for studying intestinal crosstalk
Nguyen, Thi Phuong Oanh; Vonschallen, P.; Hierlemann, Andreas; et al. (2020)
Universal scaling laws for charge-carrier interactions with quantum confinement in lead-halide perovskites
Tamarat, Philippe; Prin, Elise; Berezovska, Yuliia; et al. (2023)
Nature Communications
Lead halide perovskites open great prospects for optoelectronics and a wealth of potential applications in quantum optical and spin-based technologies. Precise knowledge of the fundamental optical and spin properties of charge-carrier complexes at the origin of their luminescence is crucial in view of the development of these applications. On nearly bulk Cesium-Lead-Bromide single perovskite nanocrystals, which are the test bench materials for next-generation devices as well as theoretical modeling, we perform low temperature magneto-optical spectroscopy to reveal their entire band-edge exciton fine structure and charge-complex binding energies. We demonstrate that the ground exciton state is dark and lays several millielectronvolts below the lowest bright exciton sublevels, which settles the debate on the bright-dark exciton level ordering in these materials. More importantly, combining these results with spectroscopic measurements on various perovskite nanocrystal compounds, we show evidence for universal scaling laws relating the exciton fine structure splitting, the trion and biexciton binding energies to the band-edge exciton energy in lead-halide perovskite nanostructures, regardless of their chemical composition. These scaling laws solely based on quantum confinement effects and dimensionless energies offer a general predictive picture for the interaction energies within charge-carrier complexes photo-generated in these emerging semiconductor nanostructures.
speedingCARs: accelerating the engineering of CAR T cells by signaling domain shuffling and single-cell sequencing
Castellanos-Rueda, Rocío; Di Roberto, Raphaël B.; Bieberich, Florian; et al. (2022)
Nature Communications
Chimeric antigen receptors (CARs) consist of an antigen-binding region fused to intracellular signaling domains, enabling customized T cell responses against targets. Despite their major role in T cell activation, effector function and persistence, only a small set of immune signaling domains have been explored. Here we present speedingCARs, an integrated method for engineering CAR T cells via signaling domain shuffling and pooled functional screening. Leveraging the inherent modularity of natural signaling domains, we generate a library of 180 unique CAR variants genomically integrated into primary human T cells by CRISPR-Cas9. In vitro tumor cell co-culture, followed by single-cell RNA sequencing (scRNA-seq) and single-cell CAR sequencing (scCAR-seq), enables high-throughput screening for identifying several variants with tumor killing properties and T cell phenotypes markedly different from standard CARs. Mapping of the CAR scRNA-seq data onto that of tumor infiltrating lymphocytes further helps guide the selection of variants. These results thus help expand the CAR signaling domain combination space, and supports speedingCARs as a tool for the engineering of CARs for potential therapeutic development.
Integrating Immune Components into Microphysiological Systems for Disease Modeling and Therapy Testing
Nguyen, Thi Phuong Oanh (2023)
This thesis describes the concept, methods of fabrication, principles of operation, and biological applications of two gravity-driven perfusion microphysiological systems (MPSs). These MPSs are envisioned as new testing tools to help bridge the translational gaps between data obtained in in-vitro two-dimensional cell cultures, in-vivo animal testing, and clinical research. Each system possesses distinct features that have been specifically introduced to support the formation and long-term in-vitro experimentation with different types of advanced cell culture models. On the one hand, the inter-species differences that are associated with animal testing are overcome by employing human cell-based cell culture models. On the other hand, microfabrication and microfluidic technologies enable to recapitulate relevant in-vivo physiological cues in vitro and to realize inter-tissue communication, which increases the physiological relevance of these systems. The MPSs introduced in this thesis are: (i) An intestine-on-chip MPS that supports the simultaneous formation of multiple in-vitro intestinal epithelial barrier (IEB) model units for modeling inflammatory bowel disease (IBD). The unique compartmentalized design of the microfluidic chip allows for culturing each on-chip IEB model unit with different types of immune cells in a spatially-separated configuration. Upon site-specific administration of inflammatory stimuli, different hallmarks of IBD were detected. The system’s potential for therapy testing was demonstrated by site-specific administration of a therapeutic compound that successfully alleviated inflammations. (ii) An immunocompetent MPS (iMPS) that enables simultaneous assessment of the efficacy and potential off-target toxicity of anti-tumor immune cells. Three-dimensional cell culture models of a solid tumor and the heart were fluidically interconnected within a microfluidic network. Free-flowing anti-tumor immune cells were circulated through the microfluidic network using gravity-driven flow, which promoted their interaction with the solid tissue models. Specific, direct immune cell-mediated anti-tumor activity was observed on chip, while a soluble factor-driven adverse effect on the heart model also became evident. By utilizing commercially available components for chip fabrication, both MPSs, presented in this thesis, can be reproducibly fabricated. The application of gravity-driven flow to maintain on-chip perfusion renders these MPSs user-friendly in their operation, enables straightforward experimental parallelization, and provides flexibility to vary and adapt the complexity of the on-chip biological models.
Immunocompetent microphysiological system for simultaneous efficacy and safety assessment of immune-cell-based anti-cancer therapies
Nguyen, Thi Phuong Oanh; Misun, Patrick; Lohasz, Christian; et al. (2022)
25th International Conference on Miniaturized Systems for Chemistry and Life Sciences (MicroTAS 2021)
Investigating the intercellular interaction between 3D gut epithelial microtissues and circulating MAIT cells using a microfluidic tilting platform
Nguyen, Thi Phuong Oanh; Misun, Patrick; Lohasz, Christian; et al. (2019)
23rd International Conference on Miniaturized Systems for Chemistry and Life Sciences (MicroTAS 2019)
Microphysiological systems constitute new, versatile tools to investigate the pathogenesis of different immunemediated inflammatory diseases – among them inflammatory bowel disease (IBD). To recapitulate more faithfully the interaction between the gut model and relevant immune cells, we adapted a commercialized microfluidic platform to co-culture three-dimensional (3D) gut epithelial microtissues (MTs) with circulating mucosalassociated invariant T (MAIT) cells in vitro in a dynamic microenvironment. This platform enables i) on-chip optical readout of specific physical interaction between 3D gut epithelial MTs and MAIT cells, and ii) supernatantbased readout of soluble cytokine signals in both, healthy and infection scenarios.
A Versatile Intestine-on-Chip System for Deciphering the Immunopathogenesis of Inflammatory Bowel Disease
Nguyen, Thi Phuong Oanh; Misun, Patrick; Hierlemann, Andreas; et al. (2024)
Advanced Healthcare Materials
The multifactorial nature of inflammatory bowel disease (IBD) necessitates reliable and practical experimental models to elucidate its etiology and pathogenesis. To model the intestinal microenvironment at the onset of IBD in vitro, it is important to incorporate relevant cellular and noncellular components before inducing stepwise pathogenic developments. A novel intestine-on-chip system for investigating multiple aspects of IBD's immunopathogenesis is presented. The system includes an array of tight and polarized barrier models formed from intestinal epithelial cells on an in-vivo-like subepithelial matrix within one week. The dynamic remodeling of the subepithelial matrix by cells or their secretome demonstrates the physiological relevance of the on-chip barrier models. The system design enables introduction of various immune cell types and inflammatory stimuli at specific locations in the same barrier model, which facilitates investigations of the distinct roles of each cell type in intestinal inflammation development. It is showed that inflammatory behavior manifests in an upregulated expression of inflammatory markers and cytokines (TNF-α). The neutralizing effect of the anti-inflammatory antibody Infliximab on levels of TNF-α and its inducible cytokines could be explicitly shown. Overall, an innovative approach to systematically developing a microphysiological system to comprehend immune-system-mediated disorders of IBD and to identify new therapeutic strategies is presented.
A modular microfluidic platform with gravity-driven flow for establishing intestinal barrier models
Nguyen, Thi Phuong Oanh; Hierlemann, Andreas; Renggli, Kasper (2019)
An Immunocompetent Microphysiological System to Simultaneously Investigate Effects of Anti-Tumor Natural Killer Cells on Tumor and Cardiac Microtissues
Nguyen, Thi Phuong Oanh; Misun, Patrick; Lohasz, Christian; et al. (2021)
Frontiers in Immunology
Existing first-line cancer therapies often fail to cope with the heterogeneity and complexity of cancers, so that new therapeutic approaches are urgently needed. Among novel alternative therapies, adoptive cell therapy (ACT) has emerged as a promising cancer treatment in recent years. The limited clinical applications of ACT, despite its advantages over standard-of-care therapies, can be attributed to (i) time-consuming and cost-intensive procedures to screen for potent anti-tumor immune cells and the corresponding targets, (ii) difficulties to translate in-vitro and animal-derived in-vivo efficacies to clinical efficacy in humans, and (iii) the lack of systemic methods for the safety assessment of ACT. Suitable experimental models and testing platforms have the potential to accelerate the development of ACT. Immunocompetent microphysiological systems (iMPS) are microfluidic platforms that enable complex interactions of advanced tissue models with different immune cell types, bridging the gap between in-vitro and in-vivo studies. Here, we present a proof-of-concept iMPS that supports a triple culture of three-dimensional (3D) colorectal tumor microtissues, 3D cardiac microtissues, and human-derived natural killer (NK) cells in the same microfluidic network. Different aspects of tumor-NK cell interactions were characterized using this iMPS including: (i) direct interaction and NK cell-mediated tumor killing, (ii) the development of an inflammatory milieu through enrichment of soluble pro-inflammatory chemokines and cytokines, and (iii) secondary effects on healthy cardiac microtissues. We found a specific NK cell-mediated tumor-killing activity and elevated levels of tumor- and NK cell-derived chemokines and cytokines, indicating crosstalk and development of an inflammatory milieu. While viability and morphological integrity of cardiac microtissues remained mostly unaffected, we were able to detect alterations in their beating behavior, which shows the potential of iMPS for both, efficacy and early safety testing of new candidate ACTs.
speedingCARs: accelerating the engineering of CAR T cells by signaling domain shuffling and single-cell sequencing
Di Roberto, Raphaël B.; Castellanos-Rueda, Rocío; Schlatter, Fabrice S.; et al. (2021)
bioRxiv
Chimeric antigen receptors (CARs) consist of an extracellular antigen-binding region fused to intracellular signaling domains, thus enabling customized T cell responses against target cells. Due to the low-throughput process of systematically designing and functionally testing CARs, only a small set of immune signaling domains have been thoroughly explored, despite their major role in T cell activation, effector function and persistence. Here, we present speedingCARs, an integrated method for engineering CAR T cells by signaling domain shuffling and functional screening by single-cell sequencing. Leveraging the inherent modularity of natural signaling domains, we generated a diverse library of 180 unique CAR variants, which were genomically integrated into primary human T cells by CRISPR-Cas9. Functional and pooled screening of the CAR T cell library was performed by co-culture with tumor cells, followed by single-cell RNA sequencing (scRNA-seq) and single-cell CAR sequencing (scCAR-seq), thus enabling high-throughput profiling of multi-dimensional cellular responses. This led to the discovery of several CAR variants that retained the ability to kill tumor cells, while also displaying diverse transcriptional signatures and T cell phenotypes. In summary, speedingCARs substantially expands and characterizes the signaling domain combinations suited for CAR design and supports the engineering of next-generation T cell therapies.

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Thi Phuong Oanh Nguyen

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