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Microfluidics based analysis of immune cell navigation modes and migration in non-linear chemokine gradients

Applicant Mehling Matthias
Number 179662
Funding scheme Ambizione
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.07.2018 - 30.06.2019
Approved amount 248'267.00
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Keywords (6)

cerebrospinal fluid; microfluidics; cell navigation; chemokine gradient; multiple sclerosis; cell migration

Lay Summary (German)

Lead
Charakterisierung der Navigation von Immunzellen in nicht-linearen Chemokin-Gradienten
Lay summary

Inhalt und Ziel des Forschungsprojekts

Die gerichtete Wanderung von Immunzellen spielt beim Aufbau von Immunreaktionen eine zentrale Rolle. Sie wird massgeblich von Chemokinen gesteuert, wenn diese als Gradienten vorliegen. Im Rahmen von Entzündungen - wie beispielsweise bei in Entzündungsherden der Multiplen Sklerose - liegen diese Chemokin-Gradienten mit grosser Wahrscheinlichkeit nicht in linearer Form vor, sondern sind durch Irregularitäten gekennzeichnet. Dies erfordert eine gewisse Persistenz der Migration in Bereichen irregulär geformter Chemokin-Gradienten.

Übergeordnetes Ziel unseres Forschungsprojekts ist es, das Migrationsverhalten von Immunzellen in irregulär geformten Chemokin-Gradienten mit Hilfe einer von uns entwickelten Microfluidics-Technik zu charakterisieren. Mit Hilfe dieser Technik werden wir untersuchen, wie Immunzellen in solchen Gradienten navigieren und welches Ausmass an Irregularität von Chemokin-Gradienten sie tolerieren können ohne dass die Fähigkeit zur gerichteten Migration eingeschränkt wird. Ausserdem werden wir das Migrationsverhalten von Immunzellen die aus dem Nervenwasser von Patienten mit Multipler Sklerose gewonnen werden charakterisieren.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts
Unser Projekt wird zum Verständnis des Migrationsverhaltens von Immunzellen auf Einzelzellebene und somit zum Verständnis adaptiver zellulärer Immunantworten beitragen. Die Untersuchung des Migrationsverhaltens von aus dem Nervenwasser isolierten Immunzellen wird zu einem verbesserten Verständnis der Multiplen Sklerose zugrundeliegenden Mechanismen führen und kann als Basis für neue Therapieansätze dienen.

 

Direct link to Lay Summary Last update: 15.12.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Nano-scale microfluidics to study 3D chemotaxis at the single cell level
Frick Corina, Dettinger Philip, Renkawitz Jörg, Jauch Annaïse, Berger Christoph T., Recher Mike, Schroeder Timm, Mehling Matthias (2018), Nano-scale microfluidics to study 3D chemotaxis at the single cell level, in PLOS ONE, 13(6), e0198330-e0198330.

Collaboration

Group / person Country
Types of collaboration
Morphodynamics of Immune Cells Group (Prof. Sixt), Institute of Science and Technology Austria Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Immunodeficiency Group (Prof. Recher), Department of Biomedicine, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Bioinformatics Core Facility (Dr. Geier), Department of Biomedicine, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Lämmermann, Max Planck Institure of Immunobiology and Genetics, Freiburg/Germany Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Systems Biology Group (Prof. Schroeder),Department of Biosystems Science and Engineering, ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Neurology Department (Prof. Kappos), University Hospital of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
154733 Microfluidics-based analysis of human T cell migration on a single cell level 01.07.2015 Ambizione

Abstract

The ability of the immune system to mount protective immune responses critically depends on precisely controlled migration and positioning of immune cells within lymphoid and non-lymphoid tissues. Migration of immune cells plays also an important role during the pathogenesis of autoimmune disorders such as multiple sclerosis. Directed migration of immune cells is governed by chemokine gradients acting as extracellular guidance cues. Challenges for chemotaxis are that gradients contain various mean concentrations migrating cells have to adapt to. Also, chemokine gradients need to be sustained and are under physiological conditions presumably not perfectly linear or exponential. They rather contain irregularities such as local changes in steepness or even circumscribed slopes that impose short gradients in the opposite direction of the main gradient. In considering how cells efficiently migrate in such gradients, two questions are particularly important: (i) How does a cell sense the direction of a chemokine gradient? and (ii) what sustains migration along potentially irregular gradients? Two major concepts have been proposed to address these questions. First, temporal sensing of gradients similar to bacteria has been suggested and, second, that spatial sensing of differences of chemokine concentrations across the cell diameter governs chemotaxis. Although consensus seems to exist that immune cells navigate in chemokine gradients by spatial sensing, so far no experimental systems with precisely controllable chemokine gradients is available to ultimately test these two hypotheses.During the last years we have developed various microfluidic devices to study migration properties of primary immune cells on a single cell level. These devices allow to generate precisely controllable stable diffusion-based and/or immobilised chemokine gradients of various shapes. This allows studying basic aspects of signal integration of migrating cells, such as the fundamental question outlined above, i.e. whether chemotaxis is governed by temporal vs. spatial sensing and how irregularities of chemokine gradients impact on persistent cell migration.The General Aim of this proposal is to assess which sensing strategies operate in immune cells navigating in chemokine gradients, and how immune cells migrate in irregular chemokine gradients. The following specific aims will be addressed:Specific Aim 1: Assessment whether temporal vs. spatial sensing governs immune cell navigation in chemokine gradients.Having developed a microfluidic system to generate precisely controllable chemokine gradients will enable us to determine which sensing mechanism operates in migrating bone marrow derived dendritic cells (BMDC) in response to chemokine gradients. Recently established genome-editing techniques in BMDCs will allow us to mechanistically assess the role of candidate molecules, e.g. G-protein coupled kinase 3 during navigation in chemokine gradients.Specific Aim 2: Define how irregularities of chemokine gradients impact on persistence of immune cell migration.These experiments will explore to which degree irregularities of chemokine gradients can be compensated by migration persistence of BMDC. These data will provide the basis for developing a computational model to understand the gradient-related requirements for efficient chemotaxis.Specific Aim 3: Relate migration-characteristics of MS cerebrospinal fluid immune cells with clinical phenotypes (“single cell functional immune profiling”)Having refined our microfluidic device to allow immobilisation of chemokines and assessment of chemotaxis in 3D environments was time-consuming and we are therefore approximately 6 months delayed with Specific Aim 4 of the original Ambizione-Proposal. We aim to continue assessing migration characteristics of CSF cells from patients with MS on a single cell level. Linking this information with clinical data carries the potential to establish a functional immune profile (functional biomarker) comprising insight on immune cell parameters with an established role in disease pathogenesis.
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