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Mechanotransduction processes, from the cell periphery to the nucleus, in 2D versus 3D microenvironments

English title Mechanotransduction processes, from the cell periphery to the nucleus, in 2D versus 3D microenvironments
Applicant Vogel Viola
Number 156931
Funding scheme Interdisciplinary projects
Research institution Angewandte Mechanobiologie Gesundheitswissenschaften und Technologie ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Biophysics
Start/End 01.10.2014 - 30.09.2017
Approved amount 742'250.00
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All Disciplines (2)

Discipline
Biophysics
Other disciplines of Engineering Sciences

Keywords (6)

cytoplasmic-nuclear trafficking; cell adhesion; mechanobiology; mechanoregulation; nuclear processes; microtissues

Lay Summary (German)

Lead
Entschlüsseln, wie die physikalischen Eigenschaften der zellulären mikro-Umgebung Zellfunktion und Genexpression regulieren ist der «heilige Gral» der Mechanobiologie, denn die Verankerung und Wechselwirkung von Zellen mit der extrazellulären Matrix ihrer Umgebungen ist wichtig für ihr Überleben und diktiert ihr Verhalten. Während lange gedacht wurde, daß Zellen nur "einen" Mechanosensor nutzen, wissen wir heute, dass verschiedene Arten von mechanisch-regulierte Signaleinheiten existieren, von der Zellperipherie zum Zellnukleus, und somit das Zellverhalten co-regulieren.
Lay summary

In diesem Forschungsprojekt werden die folgenden Fragen adressiert:
In der Vergangenheit wurden die meisten Mechanotransduktionsmechanismen, i.e. mechanische Stimuli in biochemische Signale umgewandelt werden,  für Zellen auf flachen Oberflächen untersucht. Hier fragen wir nun, wie sich die Mechanismen verändern, wenn Zellen in künstlich strukturierten Umgebungen und in Mikrogeweben eingebettet werden. Bekannt ist bisher nur, dass Zellen sich auf flachen Oberflächen anders verhalten, als wenn sie in einem Gewebe eingebettet sind.

Um zu erforschen, wie Mechanotransduktionsprozesse verändert werden, wenn Zellen in (Mikro-) Gewebe eingebettet sind, werden wir einen integrativen Ansatz verfolgen der mehrere Längenskalen, von einzelnen Zellen zu Geweben, überbrückt.

Die Signifikanz des Forschungsprojektes ist vielfältig:
Ein grundsätzliches Verständnis der Rolle der mechanischen Kräfte bei der Regulierung der Wechselwirkungen zwischen Zellen und ihrer Umgebung ist nicht nur wissenschaftlich lohnend, sondern ist auch von entscheidender Bedeutung in der Krebsforschung und um neue Methoden in der regenerativen Medizin zu entwickeln.

Ferner und da so viele Erkrankungen mit einer Funktionsstörung der mechanosensorischen oder Mechanotransduktionmaschinerie von Zellen (Herz-Kreislauf, Krebs, Osteoporose, Laminopathien usw.) zugeordnet sind, gibt es eine starke Nachfrage nach neuen dreidimensionalen Zellkultur-Plattformen. Wenn Mechanotransduktionsprozesse von der Dimensionalität der zellulären Mikroumgebung gesteuert werden, könnte dies somit auch von hoher Bedeutung für die Schweizer Pharma-Industrie sein.
Direct link to Lay Summary Last update: 03.11.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Nanoscale invaginations of the nuclear envelope: Shedding new light on wormholes with elusive function
Ingmar Schön, Lina Aires, Jonas Ries, Viola Vogel (2017), Nanoscale invaginations of the nuclear envelope: Shedding new light on wormholes with elusive function, in Taylor & Francis Online, 1-9.
Structural Insights How PIP2 Imposes Preferred Binding Orientations of FAK at Lipid Membranes
Florian Herzog, Lukas Braun, Ingmar Schön, Viola Vogel (2017), Structural Insights How PIP2 Imposes Preferred Binding Orientations of FAK at Lipid Membranes, in Journal of Physical Chemistry B, 121(15), 3523-3535.
Gradual conversion of cellular stress patterns into pre-stressed matrix architecture during in vitro tissue growth
Cécile M. Bidan, Philip Kollmannsberger, Vanessa Gering, Sebastian Ehrig, Pascal Joly, Ansgar Peters, Viola Vogel, Peter Fratzl, John W. C. Dunlop (2016), Gradual conversion of cellular stress patterns into pre-stressed matrix architecture during in vitro tissue growth, in Journal of the Royal Society Interface, 13(118), 1-11.
Improved side chain dynamics in MARTINI simulations of protein-lipid interfaces
Florian Herzog, Lukas Braun, Ingmar Schön, Viola Vogel (2016), Improved side chain dynamics in MARTINI simulations of protein-lipid interfaces, in Journal of Chemical Theory and Computation , 12(5), 2446-2458.
Novel peptide probes to assess the tensional state of fibronectin fibers in cancer
Arnoldini S. Mosacroli A. Chabria M. Hilber M. Hertig S. Schibli R. Béhé M. Vogel V., Novel peptide probes to assess the tensional state of fibronectin fibers in cancer, in Nature Communication.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Peter Fratzl / Max-Planck-Institut für Kolloid- und Grenzflächenforschung Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Yuval Ebenstein- Department of Chemical Physics- Tel Aviv University Israel (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Stephanie Helen- Yale University Medical School United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Ingmar Schön, Department of Molecular and Cellular Therapeutics and Irish Centre for Vascular Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Bernhard Wehrle-Haller / Université de Genève, Physiologie cellulaire et métabolisme Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Lorenz Meinel/Julius-Maximilians-Universität Würzburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Matthias Lutolf- EPFL Switzerland Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Chris S. Chen. / University of Pennsylvania, Skirkanich Prof. of Innovation in Bioengineering United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Ohad Medalia, Department of Biochemistry, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Daniel Müller / ETH Basel, Dept. Biosysteme Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Juan Perilla, Beckmann Institute of Urbana-Champaign United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Simon P. Hoerstrup / Universität Zürich, Regenerative Medicine Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Chuan He- University of Chicago United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Dr. Martin Behe / Paul Scherrer Institut PSI Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Mike Dustin / New York University, Medical School United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Beth Pruitt / Stanford University; Mechanical Engineering United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Jan-Dirk Studt, Divison of Hematology, University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Multiscale Mechanochemistry & Mechanobiology from Molecular mechanisms to smart Materials Talk given at a conference Mechanobiology of Extracellular Matrix: from cells to organs 18.10.2017 Berlin, Germany Vogel Viola;
SFB 944 Symposium: Cellular microcompartments: From analytics to physiology Talk given at a conference Mechanobiology of the extracellular matrix niche 28.09.2017 Osnabrück, Germany Vogel Viola;
Swiss-Japan Biomechanics Meeting Talk given at a conference Mechanobiology of extracellular matrix: from cells to organs 16.09.2017 Zermatt, Switzerland Vogel Viola;
International Symposium on Nanoarchitectonics for Mechanobiology (ISNM) Talk given at a conference “Nanomechanics of Breaking Bonds: from concepts to the fight of bacterial infections” 29.07.2017 Tsukuba, Japan Vogel Viola;
19th IUPAB congress & 11th EBSA congress Poster Multi-scale simulations of focal adhesion kinase at PIP containing membranes 16.07.2017 Edinburgh, Great Britain and Northern Ireland Braun Lukas Patrik;
ISTH conference 2017 Poster Single Platelet Screening Platform Based on Cytoskeletal Adhesion Morphology 08.07.2017 Berlin, Germany Lickert Sebastian;
FEBS Workshop - Biological Surfaces and Interfaces: Interface Dynamics Talk given at a conference Mechanobiology: the art of forming and forcing bonds to break 04.07.2017 Sant Feliu de Guixols, Spain Vogel Viola;
Termis EU Talk given at a conference Mechanobiology of extracellular matrix: from cells to tissues 29.06.2017 Davos, Switzerland Vogel Viola;
TERMIS EU 2017 Talk given at a conference Cell geometry regulates temporal regulation of gene expression during macrophage activation 26.06.2017 Davos, Switzerland Jain Nikhil;
CLINAM – 10th EuropeanConference for Clinical Nanomedicine Talk given at a conference Mechanobiology Matters: Reassessing our Promises in Nanomedicine 06.06.2017 Basel, Switzerland Vogel Viola;
Gordon Research Conference on Tissue Repair & Regeneration Talk given at a conference Mechanobiology of extracellular matrix:  from cells to tissues 06.06.2017 New London, United States of America Vogel Viola;
Annual Meeting of the French Society for ECM Biology Talk given at a conference Mechanobiology of extracellular matrix fibers 17.03.2017 Marseille, France Vogel Viola;
Annual Meeting of the German Society for Matrix Biology “Frontiers in Matrix Biology Talk given at a conference Mechanobiology of extracellular matrix 09.03.2017 Köln, Germany Vogel Viola;
UCL's Institute for the Physics of Living Systems (IPLS) Talk given at a conference Mechanobiology:   how our immune cells fight bacterial infections 03.02.2017 London, Great Britain and Northern Ireland Vogel Viola;
PSI Seminar Individual talk Peptides to decipher the mechanobiology of extracellular matrix 27.10.2016 Villigen, Switzerland Vogel Viola;
Cell Matrix – New advances in probing cell-ECM interactions Talk given at a conference Nanoprobes to decipher the mechanobiology of extracellular matrix 20.10.2016 Berlin, Germany Vogel Viola;
Picoquant 22nd International Workshop on “Single Molecule Spectroscopy and Super-resolution Microscopy in the Life Sciences” Talk given at a conference Mechanobiology: from single molecules to desease 15.09.2016 Berlin, Germany Vogel Viola;
EMBO Talk given at a conference Molecular sensing of the environment“ Mechanical Reciprocity Between Engineered Environments and the Cell Nucleus 13.09.2016 Mannheim, Germany Vogel Viola;
IRI Colloquium “Mechanobiology Talk given at a conference Mechanical aspects in the fight of immune cells with bacterial infections 01.09.2016 Berlin, Germany Vogel Viola;
GRC: Musculoskeletal Biology and Bioengineering Talk given at a conference From the Extracellular Matrix to the Nucleus 10.08.2016 Andover, United States of America Vogel Viola;
International Symposium on Nanoarchitectonics for Mechanobiology (ISNM) Talk given at a conference Mechanical Reciprocity Between Engineered Environments, Extracellular Matrix and the Cell Nucleus 28.07.2016 Tsukuba, Japan Vogel Viola;
12th International Congress of Cell Biology, “Exploring cellular structure and function” Talk given at a conference Shaping the cell nucleus by mechanical forces 23.07.2016 Prag, Czech Republic Vogel Viola;
2nd International Symposium of the TRR67 “Frontiers in Biomaterial Science Talk given at a conference Rethinking mechanotransduction mechanisms: from the ECM to the cell nucleus 24.06.2016 Leipzig, Germany Vogel Viola;
University of Nice, BioPhysics Interdisciplinary Axis of the University Individual talk Why mechanobiological aspects of the extracellular matrix matter 28.03.2016 Nizza, France Vogel Viola;
Mechanobiology: mechanism of force sensation and transduction that control cell behavior in health and disease Poster Molecular determinants of platelets spreading in health and disease 22.03.2016 Amsterdam, Netherlands Lickert Sebastian;
Biophysical Society Annual Meeting, Mechanobiology Subgroup 2016 Symposium Talk given at a conference How Mechanical Forces Regulate the Structural Polarization of the Nuclear Lamina 27.02.2016 Los Angeles, United States of America Vogel Viola;
BIH Berlin Institute of Health Symposium Talk given at a conference Mechanobiology: coupling the extracellular matrix to the cell nucleus 29.01.2016 Berlin, Germany Vogel Viola;
Symposium: Giacinto Scoles 80th birthday Talk given at a conference Stretching our imagination:  why forces matter 21.01.2016 Trieste, Italy Vogel Viola;
EMBO Workshop: Stem cell mechanobiology in development and disease Talk given at a conference Mechano-chemical signal conversion: from the extracellular matrix to the nucleus 19.10.2015 Capri, Italy Vogel Viola;
EMBO Workshop “Stem cell mechanobiology in development and disease Talk given at a conference Emerging Patterns of proliferation and ECM organization guided by force-geometry feedback during 3D microtissue growth 18.10.2015 Capri, Italy Kollmannsberger Philip Maximilian;
Stem cell mechanobiology in development and disease Poster Physico-chemical coupling: what mechanisms switch cell plasticity and thus phenotype and functional output 18.10.2015 Capri, Italy Jain Nikhil;
BioMediTech Seminar, University Tampere Individual talk Bonding, beyond biochemistry 16.10.2015 Tampere, Finland Vogel Viola;
Physics of Cells: From Molecules to Systems (PhysCell 2015) Talk given at a conference How do cells exploit mechanical forces to recognize their environments? 01.09.2015 Bad Staffelstein, Germany Vogel Viola;
PhysCell 2015  Poster Physico-chemical coupling: what mechanisms switch cell plasticity and thus phenotype and functional output? 30.08.2015 Kloster Banz, Germany Jain Nikhil;
UJF Greneble Talk given at a conference Cell-Matrix Feedback from the Single Cell to the Tissue Scale 29.06.2015 Grenoble, France Kollmannsberger Philip Maximilian;
PASC 15 Poster The effect of calcium binding on tTG 01.06.2015 Zurich, Switzerland Braun Lukas Patrik;
International Symposium “Frontiers in Chemical Sciences”, Weizmann Institute Talk given at a conference Learning from Nature: How to Engineer the Mechanical Stability of Non-Covalent bonds 26.05.2015 Rehovot, Israel Vogel Viola;
TU Eindhoven Talk given at a conference Cell-matrix feedback during tissue growth and remodeling 26.03.2015 Eindhoven, Netherlands Kollmannsberger Philip Maximilian;
Force-Gated Ion Channels”, Janelia Farm Research Campus Individual talk Structural motifs by which protein stretching switches their functions 24.03.2015 Ashburn, United States of America Vogel Viola;
Cornell University, College of Engineering Materials Science and Engineering Talk given at a conference Mechanobiology of Extracellular Matrix 04.03.2015 Ithaca, United States of America Vogel Viola;
EACR Conference Series 2014, Goodbye Flat Biology 3D Models & the Tumour Microenvironment Talk given at a conference Nanomechanics by which cancer cells interact with extracellular matrix 05.11.2014 Berlin, Germany Vogel Viola;
NanoCity 2014 Talk given at a conference The nanomechanics of breaking bonds: from concepts to the fight of bacterial 27.10.2014 Maarseen, Netherlands Vogel Viola;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media A Better Environment for Tissue Repair GEN Genetic Engineering & Biotechnology News International 2017
Media relations: print media, online media Arrestzelle für Zellen Laborjournal online International 2017
Talks/events/exhibitions SOUND OF MOLECULES – I. FIDDLE (WITH) German-speaking Switzerland 2017
Media relations: radio, television BASAR MOLEKULAR: THE TALK: Let’s TALK about Molecular Systems Engineering and other topics Radio X Basel German-speaking Switzerland 2016
New media (web, blogs, podcasts, news feeds etc.) Using Physics to Exploit Bacteria’s Mechanical Weaknesses World Economic Forum International 2016

Awards

Title Year
"Einstein BIH Visiting Fellows“ Stiftung Charité für Private Exzellenzinitiative Johanna Quandt für den Zeitraum von 1. Januar 2018 bis 31. Dezember 2020 2017
Biophysical Society Student Poster Award at the 2017 EBSA Conference 2017
SNF short Term Grant, International Exchange Program Grant 2017
Faculty Appointment; Juniorprofessor für "Computergestütze Bildanalyse" Center for Computational and Theoretical Biology Fakultät für Biologie Julius-Maximilians-Universität, Würzburg 2015

Associated projects

Number Title Start Funding scheme
170112 Acronym: Angio-Fib - How pericellular matrix orchestrates the angiogenic-to-fibrotic transition 01.11.2016 Project funding (Div. I-III)
133122 Towards simulating a cell adhesion site at angstrom resolution 01.03.2011 Project funding (Div. I-III)
175839 Mechanobiology of Extracellular Matrix 01.10.2017 Project funding (Div. I-III)

Abstract

Deciphering how physical properties of cellular microenvironments regulate cell function and gene expression is the «holy grail» in mechanobiology, as the anchorage of cells in extracellular matrix (ECM) environments is essential for their survival. While it was initially thought that cells exploit only “one” mechanosensor, we know today that different types of mechano-regulated signaling units co-regulate cell behavior and gene transcription processes. As cells exploit traction forces to sense the physical characteristics of their microenvironments, it is becoming recognized now that most proteins of force-bearing junctions have at least some functionalities that are turned on or off by mechanical forces. Mechanotransduction processes can thereby occur at various sequentially and spatially distinct levels, a notion of major interest to this proposal. We thus hypothesize here that cells respond to the dimensionality (2D versus 3D) and rigidity of their microenvironments, and that the tensile state of the cytoskeletal architecture ultimately regulates how mechanical forces impact nuclear functions. Most of this information has been derived in the past by investigating cells adhering to flat surfaces. To ask how mechanotransduction processes are altered once cells are embedded in (micro)tissues, we will pursue an integrative approach that bridges multiple length scales, from single cells on flat surfaces (2D) to (micro)tissues (3D). The mechanical strength of ECM-integrin-actin junctions at the cell periphery will be tuned by exploiting drugs and growth factors that are known to alter cell contractility (Aim 1). Either ECM crosslinkling or engineered microenvironments will then be exploited to tune the ECM fibril rigidity, architecture and composition (Aim 2). By comparing the mechanobiologal response of fibroblasts in 2D versus 3D environments, we will then ask how parameters tuned according to Aims 1&2 will impact the assembly and maturation of cell adhesion plaques (Aim 3), the cytoplasmic-nuclear shuttling of (transcription) factors from the cytoplasm to the nucleus (Aim 4), and finally the structural organization of the nuclear lamina and the association of nuclear molecules with the nuclear lamina (Aim 5). Since the formation of an actin cap is a hallmark for cells adhering to flat surfaces (2D), but not in 3D environments, we will specifically ask how mechanotransduction processes are altered by the absence of an actin cap. Both, the physical forces (compressive forces acting on the nucleus in 2D), as well as the biochemical factors (force-upregulated cytoplasmic-nuclear trafficking of proteins from adhesion plaques, as well as of transcription factors and finally mediators that e.g. colocalize in the nucleus with RNA polymerase II) have thus the potency to regulate gene transcription processes in response to the mechanical properties of a cellular microenvironment. Addressing this is not only scientifically rewarding, but is also crucial to make progress in cancer research and therapy, as ECM rigidity upregulates malignancy, as well as to advance the methods employed in tissue engineering and regenerative medicine. It also addresses the strong demand of the Pharma Industry for new 3D cell culture platforms.
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