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Searched keyword : Differential analysis

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Mapping the cell surface signature of the developing mouse heart

Cell surface protein signatures have been successful to discriminate hematopoietic progenitor populations allowing major advances in understanding blood cell production, to define pathways in hematologic malignancies and to foster new therapeutic approaches. Limited knowledge on the phenotype of cells that participate in heart formation impairs our understanding of progenitors of the cardiac cell lineages and their eventual persistence in the adult organ. As a consequence, therapies to restore heart function after injury have been unsuccessful. A number of membrane proteins have been identified on cardiomyocytes; on cardiac fibroblasts; and on endothelial cells, however a multi-parametric analysis of the phenotype of the different cardiac cell compartments along development is still missing. We combined multi-parametric flow cytometry with transcriptional characterization, based on well-known gene expression patterns, to describe major cardiac cell-subsets. The expression of CD24, CD54, Sca-1 and CD90 allowed defining cardiac populations in the non-hematopoietic and non-endothelial cell fraction by flow cytometry. Transcriptional profiling of the sorted populations enabled the identification of cardiomyocytes, in the CD24+ population, while differential expression of CD54, Sca-1 and CD90 defined four cardiac stromal compartments. The identified subsets exhibited specific distributions in three analyzed regions (atria, auriculo-ventricular junction and ventricles). We have thus identified a panel of surface markers, some of which novel in the cardiac context, that allowed assigning surface signatures to different cellular fractions by their unique transcriptional profiles. This work is the foundation for comprehensive studies on the role of different cell fractions by their unique transcriptional profiles.

Project status : Closed

Characterisation of skeletal muscle stem cell properties in distinct physiological states

Stem cells are defined by their is their capacity for self-renewal and differentiation. Some adult tissues maintain a reservoir of stem cells, that generally reside within specialized microenvironments, known as stem cell niches, that regulate their behaviour. Skeletal muscle stem (satellite) cells are quiescent in homeostatic conditions in adults, and they are activated after muscle injury, when they re-enter the cell cycle, proliferate and differentiate into myoblasts, which will then fuse to form new muscle fibers. Satellite cells express the paired/homeodomain gene Pax7, which plays a critical role in satellite cell maintenance postnatally. Numerous experiments have shown that the skeletal muscle stem cell population is heterogeneous, therefore like many other stem cell systems, characterising the stem cell states is a major objective. In our laboratory, a reversible dormant cell state was identified, correspondent to a Pax7Hi quiescent subpopulation (top 10% of the Pax7-nGFP+ cells isolated from the transgenic mouse model Tg:Pax7-nGFP) with a lower metabolic activity and longer lag for the first cell division compared to Pax7Lo cells [1]. Muscle stem cells that survive for extended periods post-mortem are also dormant, suggesting that this property, in addition to anoxia [2] contributes to their viability. Therefore, different physiological states are associated with distinct cell states of muscle stem cells. Metabolism could play a critical role in dictating whether a cell remains quiescent, proliferates or differentiates. Stem cell metabolic plasticity in homeostasis and differentiation, as well as during cell reprogramming, is well described in different cell systems. However, unanswered questions remain regarding the metabolic regulation of satellite cell biology and skeletal muscle regeneration. In this project, we will investigate the behaviour of muscle stem cells in distinct physiological states, especially post-mortem and aging.

Project status : Closed

A long-term mission for an assigned CIH-embedded bioinformatician to provide bioinformatic support to the CIH community

The Center for Human Immunology (CIH) supports researchers involved in translational research projects by providing access to 16 different cutting edge technologies. Currently, the CIH hosts over 60 scientific projects coming from 8 departments of the Institut Pastuer and 5 external teams. In order to respond to the growing needs of these projects in the area of single cell analysis, the CIH has introduced a significant number of single-cell/single-molecule technologies over the past 2-3 years. These new technologies, such as the Personal Genome Machine (PGM) and Ion Proton sequencers, iSCAN microarray scanner, Nanostring technology for transcriptomics profiling and real-time PCR machine BioMark, give rise to large datasets with high dimensionality. Such trend, in terms of data complexity, is also true for flow cytometry technologies (currently reaching over 20 parameters per cell). The exploration of this data is generally beyond the scope of scientists involved in translational research projects. In order to maximize the research outcomes obtained from the analysis of these rich datasets, and to ensure that the full potential of our technologies can be served to the users of the CIH, we would require a proximity bioinformatics support. A CIH-embedded bioinformatician would: 1) design and implement standard analysis pipelines for each of the data-rich technologies of the CIH; 2) provide regular ‘bioinformatics clinics’ to allow scientists the possibility to customize standard pipelines to their specific needs; 3) run trainings on the ‘R software’ platform and other data analysis tools (such as Qlucore) of interest for the CIH users. The objective would be to empower the users to run exploratory analysis by themselves, and to teach good practices in terms of data management and data analysis.    

Project status : In Progress

RNAseq analysis-gene ontology enrichment Clostridium tetani

Project status : Awaiting Publication

Study of the early pathogenesis during Lassa fever in cynomolgus monkeys and its correlation with the outcome

Because of their increasing incidence, dramatic severity, lack of treatment or vaccine, complicated diagnosis, misreading of the pathogenesis, and need for a maximum containment, Viral Hemorrhagic Fevers (VHF) constitute a major public health problem. There is therefore an urgent need to further study VHF to understand the pathogenesis of the severe disease and the host responses involved in their control or in the dramatic damages. Among VHF, Lassa fever (LF) is probably the most worrying one because of its endemicity and the large number of cases. LF is caused by the Old-World arenavirus Lassa virus (LASV). It is endemic to West Africa and is responsible for 300,000 cases and 5,000 to 6,000 deaths each year. We propose here to study the pathogenesis of VHF by using LF in cynomolgus monkeys as a paradigm, with a particular emphasis on the very early events. The viral tropism, pathophysiological mechanisms, and immune responses will be studied during the course of infection, including the incubation period. Powerful approaches will be used to (1) identify early biological markers of infection, to be able to confirm infection and isolate patients; (2) determine the viral tropism and dynamics during the course of infection to understand the natural history of virus into its host. (3) characterize the early pathogenic events that lead to the severe hemorrhagic syndrome to fully understand the pathophysiogenesis of VHF and identify new therapeutic targets. (4) identify the immune responses involved in the control of infection or in the fatal outcome, to reveal the involvement of immunopathological mechanisms and help to design a vaccine approach. This ambitious and unprecedented project will allow to develop therapeutic and prophylactic approaches but also to identify early biological markers of infection and improve the early diagnosis to optimize the management of outbreaks in the field and increase the survival rate in patients.

Project status : In Progress

Exploring immunological mechanisms of human graft-verus-host disease after hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematologic malignancies. The main therapeutic benefit derives both from the ability to treat patients with intensive chemotherapy and from a potent graft-versus-leukemia (GVL) effect mediated by donor T lymphocytes. Unfortunately, in some patients, donor T cells also attack host normal tissues, giving rise to graft-versus-host disease (GVHD). GVHD prevalence is between 40-80% depending on patient and transplantation characteristics and GVHD remains the main cause of non-relapse morbidity and mortality. Despite the advances in the field of HSCT and GVHD prophylaxis, disease processes in humans remain poorly understood, and the lack of biomarkers for the early diagnosis and prognosis of GVHD contributes to the high mortality of the disease. The objective of the study is to investigate the cellular and molecular mechanisms involved in the immune reconstitution after transplantation and to explore the mechanisms of acute GVHD. For three independent cohorts of donor-recipient pairs, blood samples were collected from the all the donors before transplantation and for the respective recipients either at GVHD onset or at the Day 30 or Day 90 for recipients that did not develop GVHD. Donors and recipients’ samples were analyzed using different approaches: spectral flow cytometry to investigate the cellular correlates of immune reconstitution after HSCT and of GVHD onset, gene expression analysis by NanoString technology to assess the molecular profile of immune cell populations important for GVHD development (CD4+ T cells, CD8+ T cells, NK cells and monocytes) as well as a metabolomics profiling of serum samples using mass spectrometry.

Project status : Closed

Defining Shigella-targeting of human lamina propria mononuclear cells using CyTOF technology

Invasion of human intestinal epithelial cells by Shigella flexneri is secondary to the delivery of bacterial effectors into the host cell cytoplasm via a type III secretion system (T3SS). By using a beta-lactamase reporter tool we observed that in contrast to the epithelium, human lymphocytes are mainly targeted by injection of T3SS effectors not resulting in subsequent cell invasion (Pinaud et al., 2017). Furthermore, we observed that the targeting process, in form of successful injection of effectors into the host cell, is dependent on glycan-glycan interactions between bacterial and host cell surfaces rendering the targeting process to be dependent on the activation state of the host cell (Belotserkovsky et al., 2018). CyTOF technology is a research tool used for phenotypic analysis of complex cell population allowing for the simultaneous labelling of up to 40 different surface and intracellular marker without issues of compensation as present in regular flow cytometry (van Unen et al., 2016). Using CyTOF technology and the beta-lactamase reporter tool, we will perform a detailed analysis of Shigella targeting in a complex cell population using human lamina propria mononuclear cells (LPMCs), isolated from human colon explants. Analysis will address the question if specific cellular subsets are preferentially targeted in the intestinal environment and if this differs from targeting of peripheral blood mononuclear cells (PBMCs) diverging in their immune phenotypes and cellular activation.

Project status : Closed