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Purinergic control of innate lymphoid cells in liver injury and repair

English title Purinergic control of innate lymphoid cells in liver injury and repair
Applicant Beldi Guido
Number 166594
Funding scheme Project funding
Research institution Klinik und Poliklinik für Viszerale und Transplantationschirurgie Inselspital
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.04.2016 - 31.03.2019
Approved amount 390'110.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Pathophysiology

Keywords (5)

ectonucleotidases; Interleukin-22; P2X1; Liver regeneration; Innate lymphoid cells

Lay Summary (German)

Lead
Chirurgie bietet die einzige Möglichkeit auf Heilung bei Patienten mit Lebermetastasen oder primären Lebertumoren. Grenzen der Leberchirurgie zu erweitern würde es ermöglichen, mehr Patienten mit kurativer Absicht chirurgisch zu behandeln.Adenosin-triphosphat (ATP) wird durch gestresste Zellen in die Umgebung freigesetzt. In diesem Projekt wird untersucht ob extrazelluläres ATP relevante immunologische Funktionen der Leber beeinflusst und somit für Resultat nach Leberchirurgie von Relevanz sein kann.
Lay summary

Chirurgie bietet die einzige Möglichkeit auf langfristige Heilung bei Patienten mit Lebermetastasen oder primären Lebertumoren. Die Voraussetzung für eine erfolgreiche Leberchirurgie ist die optimale Regeneration der Leber. Nach der Entfernung eines Grossteils der Leber kann die restliche Leber bis zur ursprünglichen Grösse nachwachsen. Indem die Leberregeneration besser verstanden wird können die Grenzen der Leberchirurgie erweitert werde. Dies würde den Ärzten erlauben, mehr Patienten eine vollständige Entfernung von Tumoren anzubieten.

Neben den primären Leberzellen wird die Leberregeneration durch eine Vielzahl von anderen Zellen zum Beispiel speziellen Immunzellen der Leber beeinflusst. Wie diese Zellen durch Adenosin-triphosphat (ATP) reguliert wird, wird in diesem Projekt untersucht.

 ATP ist der universelle Energieträger der menschlichen Zelle. Bei zellulärem Stress, wie er zum Beispiel während einem chirurgischen Eingriff vorkommt, wird ATP aus der Zelle freigesetzt. Dieses freigesetzte und auch in der Blutbahn zirkulierende ATP reguliert relevante immunologische und nicht-immunologische Prozesse im Körper.

In dem vorliegenden Projekt untersuchen wir primär, wie ATP freigsetzt wird und wie freies extrazelluläres ATP auf die Funktion von Immunzellen der Leber auswirkt. In einem zweiten Schritt wird untersucht ob die veränderte Funktion dieser Immunzellen den Ausgang einer Leber-Operation beeinflusst.

Aus diesen Erkenntnissen würden sich neue therapeutische Optionen ergeben da ATP Derivate bereits synthetisiert wurden und für therapeutische Zwecke getestet werden könnten.

Direct link to Lay Summary Last update: 27.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Bayesian correlation is a robust gene similarity measure for single-cell RNA-seq data
Sanchez-Taltavull Daniel, Perkins Theodore J, Dommann Noelle, Melin Nicolas, Keogh Adrian, Candinas Daniel, Stroka Deborah, Beldi Guido (2020), Bayesian correlation is a robust gene similarity measure for single-cell RNA-seq data, in NAR Genomics and Bioinformatics, 2(1), 1-15.
Connexin-43-dependent ATP release mediates macrophage activation during sepsis
Dosch Michel, Zindel Joël, Jebbawi Fadi, Melin Nicolas, Sanchez-Taltavull Daniel, Stroka Deborah, Candinas Daniel, Beldi Guido (2019), Connexin-43-dependent ATP release mediates macrophage activation during sepsis, in eLife, 8, 1-24.
Immunotherapy of alveolar echinococcosis via PD-1/PD-L1 immune checkpoint blockade in mice
Wang Junhua, Jebbawi Fadi, Bellanger Anne-Pauline, Beldi Guido, Millon Laurence, Gottstein Bruno (2018), Immunotherapy of alveolar echinococcosis via PD-1/PD-L1 immune checkpoint blockade in mice, in Parasite Immunology, 40(12), e12596-e12596.
Perioperative von Willebrand factor dynamics are associated with liver regeneration and predict outcome after liver resection
Starlinger Patrick, Pereyra David, Haegele Stefanie, Braeuer Paul, Oehlberger Lukas, Primavesi Florian, Kohler Andreas, Offensperger Florian, Reiberger Thomas, Ferlitsch Arnulf, Messner Barbara, Beldi Guido, Staettner Stefan, Brostjan Christine, Gruenberger Thomas (2018), Perioperative von Willebrand factor dynamics are associated with liver regeneration and predict outcome after liver resection, in Hepatology, 67(4), 1516-1530.
Mechanisms of ATP Release by Inflammatory Cells
Dosch Michel, Gerber Joël, Jebbawi Fadi, Beldi Guido (2018), Mechanisms of ATP Release by Inflammatory Cells, in International Journal of Molecular Sciences, 19(4), 1222-1222.
P2X1-regulated IL-22 secretion by innate lymphoid cells is required for efficient liver regenerationHepatology, Vol. XX, NO. X, 2016 Kudira et al.
Kudira Ramesh, Malinka Thomas, Kohler Andreas, Dosch Michel, de Agüero Mercedes Gomez, Melin Nicolas, Haegele Stefanie, Starlinger Patrick, Maharjan Niran, Saxena Smita, Keogh Adrian, Stroka Deborah, Candinas Daniel, Beldi Guido (2016), P2X1-regulated IL-22 secretion by innate lymphoid cells is required for efficient liver regenerationHepatology, Vol. XX, NO. X, 2016 Kudira et al., in Hepatology, 63(6), 2004-2017.

Datasets

Bayesian Correlation is a robust similarity measure for single cell RNA-seq data

Author Sanchez-Taltavull, Danie
Publication date 31.12.2019
Persistent Identifier (PID) GSE134134
Repository GEO
Abstract
Single-cell analysis of the transcriptome deepens our understanding of an individual cell's contribution to its microenvironment. Using single-cell analysis to study complex biological processes requires state-of-the-art computational tools. Assessing similarity is highly important for bioinformatics algorithms in order to determine correlations between biological information. Similarity can appear by chance, particularly for low expressed entities. This is especially relevant in single cell RNA-seq (scRNA-seq) because the read counts obtained are lower compared to bulk RNA-sequencing and therefore classic bioinformatics tools are insufficient to obtain reproducible results. Recently, a Bayesian correlation scheme, that assigns low correlation values to correlations coming from low expressed genes, has been proposed to assess similarity for bulk RNA-seq and miRNA. This Bayesian method uses a prior distribution before using empirical evidence. Our goal was to extend the properties of this Bayesian correlation scheme to scRNA-seq data. We assessed 3 ways to compute similarity. First, we computed the similarity of each pair of genes over all cells. Second, we identified specific cell populations and computed the correlation in those specific cells. Third, we computed the similarity of each pair of genes over all clusters, by including the total mRNA expression in those cells. To study the effect of the number of cells on the method, we did not rely on simulated data, we generated 4 scRNA-seq mouse liver cell libraries with a varying number of input cells. Results: We show that Bayesian correlations are more reproducible than Pearson correlations in all the scenarios studied. Compared to Pearson correlations, Bayesian correlations have a smaller dependence on the number of input cells. We demonstrate that the Bayesian correlation algorithm assigns high similarity values to genes with a biological relevance in a specific population. Significance: Our results demonstrate that Bayesian correlation is a robust similarity measure for scRNA-seq datasets. The Bayesian method allows researchers to study similarity between pairs of genes without discarding low expressed entities and to minimize biasing the results by fake correlations. Taken together, using our method of Bayesian correlation the reproducibility of scRNA-seq experiments is increased significantly.

Collaboration

Group / person Country
Types of collaboration
Prof. Stephan Jakob, Instensive Care Medicine, Bern University Hospital Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Andrew Macpherson, Department of Clinical Research, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Simon C. Robson, Liver and Transplant Centers, BIDMC, Harvard Medical School, Boston United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Dominik Obrist, ARTORG Center, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
- Industry/business/other use-inspired collaboration
Prof. Linda F. Thompson, University of Oklahoma, USA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Dr. Philippe Krebs, Institute of Pathology, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
Prof. Brigitta Stockinger, The Francis Crick Institute, London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Francesco Di Virgilio, Universita di Ferrara Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
19th international congress of mucosal immunology Talk given at a conference Hepatic innate lymphoid cells prevent from 16.07.2019 Brisbane, Australia Beldi Guido;
Mucosal immunology course & symposium Talk given at a conference The regenerating liver is vulnerable to lymph circulating intestinal bacteria 17.07.2018 Oxford, Great Britain and Northern Ireland Beldi Guido;
EASL Meeting: Gut Liver Axis Talk given at a conference The Regenerating Liver is Vulnerable to Lymph circulating Intestinal Bacteria 07.06.2018 Leuven, Belgium Beldi Guido;
Annual Meeting Swiss Society of Surgery Talk given at a conference The regenerating liver is vulnerable to lymph circulating intestinal bacteria 16.05.2018 Basel, Switzerland Beldi Guido;
Annual Meeting Swiss Society of Surgery Individual talk Hepatocellular connexin 43 expression mediates local ATP release 16.05.2018 Basel, Switzerland Beldi Guido;
Annual Meeting Swiss Society of Surgery Talk given at a conference Checkpoint blockade improves outcome in a mouse model of hepatic alveolar echinococcosis infection via maintenance of innate and adaptive immune balance 16.05.2018 Basel, Switzerland Beldi Guido;
Annual Meeting German Surgical Society Talk given at a conference Macrophages regulate outcome of sepsis via connexin 43 dependent ATP release 18.04.2018 Berlin, Germany Beldi Guido;
Annual Meeting Swiss Society of Surgery Talk given at a conference Connexin 43 mediated ATP release as a new therapeutic target for sepsis? 31.05.2017 Bern, Switzerland Beldi Guido;
Annual Meeting Swiss Society of Surgery Talk given at a conference Portal inflow restriction enhances liver regeneration and decreases liver injury after major liver resection 31.05.2017 Bern, Switzerland Beldi Guido;


Awards

Title Year
Research prize Annual Congress Bern, Swiss Societey of Surgery 2017

Associated projects

Number Title Start Funding scheme
130816 Natural killer cell function after liver resection: the role of extracellular ATP 01.04.2010 Project funding
183501 Installing a Hyperion CyTOF mass cytometry platform for high-dimensional single cell analysis at the University of Bern 01.10.2019 R'EQUIP
115700 CD39/NTPDase1 expression by Natural Killer T cells modulates hepatic inflammation and oncogenesis 01.01.2007 SFGBM Fellowships for advanced researchers
112764 Modulation of hepatocyte and sinusoidal endothelial cell responses by ectonucleotidase during liver regeneration 01.01.2006 Fellowships for prospective researchers
146986 NTPDase1/CD39 and innate lymphoid cells in liver injury and repair 01.04.2013 Project funding

Abstract

BackgroundThe prerequisite for successful and safe liver surgery is the optimal repair and regeneration of the remaining hepatic tissue. Liver regeneration depends on cellular cross-talk that is coordinated by autocrine and paracrine signals. Nucleotides such as adenosine triphosphate (ATP) are released during liver injury and activate specific purinergic (P2) receptors that are present on the surface of all immune cells. We have shown that extracellular ATP is released within minutes in patients undergoing liver resection and modulates the function of innate immune cells. A recently identified cellular group of the immune system are innate immune cells (ILC) that expand in the regenerating liver. The composition and the phenotype of ILC that circulate in the hepatic sinusoids is different to other organs, however, fate and function of these cell types in the liver remain poorly understood. ILC exhibit potent effector functions including the secretion of cytokines such as interleukin 22 (IL-22), which is a potent unidirectional mediator between immune and parenchymal cells and is required for efficient liver regeneration. We have shown that extracellular ATP impacts on the regenerating liver via the modulation of IL-22 by ILC, potentially via the receptor P2X1. From these studies, however, important questions remain to be addressed. In particular we first aim to describe mechanisms that are required for hepatocellular ATP release in the regenerating liver. Second, the phenotype of hepatic innate lymphoid cells will be described in detail and contrasted to other organs. Third, we will investigate by what mechanisms extracellular nucleotides impact on the function of hepatic ILC during homeostasis and injury and repair. Hypothesis: Extracellular ATP critically modulates the function of hepatic ILC in liver injury and repair.Specific aims•Determine the mechanism of hepatocellular ATP release in response to surgical liver injury•Describe functions and fate of ILC in the liver •Determine the mechanism of purinergic signalling on ILC functions in response to injurySignificanceRegulation of innate immunity that contributes to liver injury and hepatocellular proliferation in the regenerating liver will be investigated in this proposal. In particular, fate and function of liver specific ILC fractions and the mechanisms of its control by extracellular nucleotides will be elucidated in this project. The insight of ATP mediated regulation of the function ILC are likely to be of relevance to organs other than the liver. The results could lead to new avenues within disease models that depend upon innate immune mechanism and eventually to novel therapeutic modalities for the patient undergoing liver surgery.
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