The Consortium

To tackle this ambitious program, we have formed a unique consortium, combining leading groups in experimental and theoretical biophysics with leading biology groups in the area of mechanosensing and stem cell research. Together, we will develop novel methods to simultaneously image cells and matrices, and measure their local and global mechanical properties. Through quantitative experiments of cells attached to 2D nano-structured substrates and embedded in 3D matrices of controlled composition, we will examine how non-equilibrium forces generated by individual cells control matrix organization and mechanics, and how the mechanics of the matrix affect single-cell force generation. These mechanical measurements will be backed by simultaneous biochemical and cell biological analysis of cell adhesion, motility, and differentiation in the labs of our biology-oriented team members. Theoretical modeling, both analytical and computational, will allow us to unravel the fundamental principles underlying mechanosensing and force production. In addition to using fibroblasts engineered for manipulation of cell-matrix adhesion structures, the program has a particular focus on stem cells given that mechanical cues emerged as decisive parameter in stem cell lineage commitment and differentiation.

Erik Danen
Leiden-Amsterdam Center for Drug Research, Leiden University
Danen’s group uses molecular biology, biochemistry, and (live) cell imaging in 2D and 3D environments to study bi-directional signal transmission through integrins. Using genetically engineered cell systems they found that distinct integrin subtypes binding the same ligand, differently couple ECM to cytoskeleton, with striking effects on cell migration and proliferation.
Marileen Dogterom
FOM Institute AMOLF, Amsterdam
Dogterom’s group specializes in the study of force generation by dynamic cytoskeletal polymers. In recent years several in vitro and in vivo methods have been developed to study force generation at a single filament level, both in the absence and presence of relevant regulatory proteins. She is the recipient of a 2007 NWO VICI award.
Elly Hol
Utrecht Medical Center, Department of Translational Neuroscience
Hol is heading the group “Astrocyte Biology & Neurodegeneration”, which focuses on the cell and molecular biology of reactive and neurogenic astrocytes. She has discovered a unique cytoskeletal identifier for human adult neural stem cells. She is a recipient of a 2008 NWO VICI-award.
Davide Iannuzzi
Physics Institute, Free University Amsterdam
Iannuzzi’s group is focused on developing innovative micromachined transducers (e.g. fiber-top technology) and methods for the investigation of fundamental phenomena at the micron scale (e.g., the Casimir force). He is recipient of a 2004 NWO VIDI award and of a 2008 ERC Starting Independent Research Grant.
Gijsje Koenderink
FOM Institute AMOLF, Amsterdam
Koenderink leads an experimental research group focusing on the soft condensed matter physics of cells and tissues. Her group employs rheology, particle tracking microrheology, optical tweezers, and optical microscopy to study biomimetic model systems of intracellular and extracellular proteins. She is a recent recipient of an NWO VIDI (2008) award.
Fred MacKintosh
Physics Institute, Free University Amsterdam
The MacKintosh group develops theoretical models of cytoskeletal and other biopolymer networks, using both analytic and simulation methods. Our recent focus has been on nonlinear elastic and non-equilibrium mechanics and dynamics of motor-activated gels. This work is often done in close collaboration with experiment.
Christine Mummery
Leiden University Medical Center
Mummery leads a stem cell research group that carries out basic cell biology on derivative human cardiomyocytes, vascular endothelial and smooth muscle cells and develops these into drug screen modalities in vitro.
Robert Passier
Leiden University Medical Center
Passier works on molecular regulation of cardiac differentiation and disease in human pluripotent stem cells.
Thomas Schmidt (coordinator)
Leiden Institute of Physics, Leiden University
Schmidt’s group is specialized on ultrasensitive superresolution microsopy techniques applied to problems in cellular signaling. In particular, processes in gradient sensing and chemotaxis are investigated. In recent years the group developed biomimetic systems for understanding cellular processes on a mechanistic basis.
Cornelis Storm
Dutch Polymer Institute, Eindhoven University of Technology
Storm’s “Function and Soft Mechanics of Biomaterials” group focuses on the analytical and numerical modeling of soft biological materials such as cytoskeletal and extracellular polymer networks and lipid bilayer membranes. Recent focus has been on collagenous materials and composite filamentous networks.

Associated members

Dennis Discher
Penn Engineering, University of Pennsylvania
Discher’s group focuses on making and characterizing soft materials that help clarify physical determinants of cell adhesion, signaling, cytoskeleton, nucleus, and differentiation. Recent work with stem cells shows that (i) matrix elasticity can influence cytoskeleton ‘order parameters’, (ii) Stem cell nuclei stiffen as cells differentiate, and (iii) Cytoskeleton proteins within cells undergo folding-unfolding transitions that depend on external forces as well as cell-generated forces. Recent work on the highly dynamic process of phagocytosis identifies a key switch in force generation when a phagocyte decides to eat something ‘foreign’ and leave ‘self’ alone. Much of the work on cell forces and mechanics is done in consultation with theory.
Paul Janmey
Penn Medicine, University of Pennsylvania
Janmey's group focuses on experimental measurement of cytoskeletal and extracellular matrix rheology, on the biochemistry that regulates their formation, and on the interplay between matrix and cell stiffness in vivo. Recent work shows that many cell types tune their own stiffness to match that of their surroundings and that changes in matrix stiffness can have profound effect on cell growth and division, especially in stem cells. Much of this work is done in close collaboration with theorists.
Claire Wyman
Department Cell Biology and Genetics, Erasmus University Medical Center
Wyman's group is interested in unraveling the mechanisms of genome maintenance. In particular, the groups works on the mechanism of homologous recombination and processes that relate to mismatch repair and interstrand DNA crosslink repair. Dr Wyman is our external advisor helping us to shape the program.

Collaborators

Emrah Balcioglu Emrah Balcioglu, PhD student
Leiden-Amsterdam Center for Drug Research, Leiden University
Project: Inside-out and outside-in force transmission through distinct integrin receptors.
Morris Cui, postdoc
Free University Amsterdam, Amsterdam
Project: The fiber-top AFM for deep-tissue stimulation.
Dominique Donato Dominique Donato, postdoc
Leiden Institute of Physics, Leiden University
Project: Regulation of integrin-mediated mechanosensing and mechanotransduction by the docking protein, p130Cas.
Hedde van Hoorn, PhD student
Leiden Institute of Physics, Leiden University
Project: Connection of mechnosensing to the dynamics of the actin skeleton.
Karin Jansen, PhD student
FOM Institute AMOLF, Amsterdam
Project: Mechanosensing and force generation of cells embedded in three-dimensional model extracellular matrices, using traction force microscopy, optical tweezers and rheology.
Elizaveta Novikova, PhD student
Eindhoven University of Technology
Project: A numerical and analytical survey of stress and strain propagation across the cell membrane, between extra- and intracellular filamentous networks.
Marcelo Ribeiro, PhD student
Leiden University Medical Center
Project: Generating cardiac disease models using human pluripotent stem cells.
Sophie Roth, postdoc
FOM Institute AMOLF, Amsterdam
Project: Development of biomimetic systems that simulate the outside-in coupling.
Oscar Stassen, PhD student
Netherlands Institute for Neuroscience, Amsterdam
Project: Molecular and cellular responses of astrocytes and neural stem cells induced by a mechanical force.
Olga Iedaltseva, PhD student
Leiden University
Project: Force sensing and transmission in stem cell fate decisions.

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