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