The unique physical properties of VIF, including the combination of high flexibility with very high resistance to breakage, lead to strain-stiffening rheology over a large strain range that can combine with the stiffer, but more brittle, crosslinked actin network, especially at the cell cortex, to control cell mechanics in a highly localized and rapidly tunable manner (1,2). Figure 1 shows how actin networks (4 mg/ml) crosslinked by filamin stiffen at small strains, but still break at strains less than 20%. Vimentin networks continue to strain-stiffen at large strains and resist breakage. Synthetic hydrogels like polyacrylamide exhibit only linear elasticity. The nonlinear elasticity of VIF networks means that these networks stiffen when tension is applied to the filament strands either by externally or internally generated stresses. The active interface between VIF and microtubules mediated by both dynein and kinesin motors (3) can generate internal pre-stress that stiffens VIF networks and the integrated cytoskeleton. Most studies of cortical cell stiffness have emphasized the contribution of actin networks, because, at low strains, in vitro crosslinked actin forms the stiffest networks and because actin is most concentrated at focal adhesion sites and the cell surface where probes such as optically and magnetically manipulated beads, atomic force microscope tips, and calibrated glass fibers attach. Even in measurements designed to test the stiffness near the cell surface or lamellipodium, depolymerization of actin and microtubules by latrunculin and colchicine does not decrease the cell's elastic modulus more than a factor of 3. Cells from vimentin null mice are 40% softer than corresponding cells from wild type animals when measured by magnetic twisting rheometry (4). Consistent with the strain-stiffening effect of VIF, stiffness differences between wt and vim'''cells increase with increasing deformation (5). This effect on global cell stiffness is consistent with a recent multi-scale simulation study (6). The finding that oxidized LDL increases human endothelial cell stiffness coincident with a reorganization of the VIF network (7) suggests that local and temporal changes in VIF contribute to the stiffness-related changes in human disease. The contribution of VIF to cell stiffness need not result simply from the rheology of pure VIF networks since in the cell VIFs interdigitate with actin filaments and microtubules and, in the crowded context of the cytoskeleton, both steric and biochemical interactions contribute to the mechanical response. An example of the synergistic rheological response of composite networks formed by both VIF and F-actin is shown in Figure 2. Here the stress resulting from increasing strain is plotted for equal weight concentrations (1 mg/ml) of purified F-actin filament types. At these relatively low concentrations F-actin and vimentin form weak networks, but their combination is much stronger than the sum of its parts (8), and the upward curvature of the stress-strain plot illustrates the stiffening with increasing deformation characteristic of IF networks (1). At the higher cellular concentrations of F-actin and vimentin (generally more than 10 mg/ml) the local stiffening, especially at large.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CB-D (40))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
United States
Zip Code
Prakadan, Sanjay M; Shalek, Alex K; Weitz, David A (2017) Scaling by shrinking: empowering single-cell 'omics' with microfluidic devices. Nat Rev Genet 18:345-361
Guo, Ming; Pegoraro, Adrian F; Mao, Angelo et al. (2017) Cell volume change through water efflux impacts cell stiffness and stem cell fate. Proc Natl Acad Sci U S A 114:E8618-E8627
Zaritsky, Assaf; Obolski, Uri; Gan, Zhuo et al. (2017) Decoupling global biases and local interactions between cell biological variables. Elife 6:
Costigliola, Nancy; Ding, Liya; Burckhardt, Christoph J et al. (2017) Vimentin fibers orient traction stress. Proc Natl Acad Sci U S A 114:5195-5200
Ridge, Karen M; Shumaker, Dale; Robert, Amélie et al. (2016) Methods for Determining the Cellular Functions of Vimentin Intermediate Filaments. Methods Enzymol 568:389-426
Charrier, Elisabeth E; Janmey, Paul A (2016) Mechanical Properties of Intermediate Filament Proteins. Methods Enzymol 568:35-57
Israeli, Eitan; Dryanovski, Dilyan I; Schumacker, Paul T et al. (2016) Intermediate filament aggregates cause mitochondrial dysmotility and increase energy demands in giant axonal neuropathy. Hum Mol Genet 25:2143-2157
Lowery, Jason; Jain, Nikhil; Kuczmarski, Edward R et al. (2016) Abnormal intermediate filament organization alters mitochondrial motility in giant axonal neuropathy fibroblasts. Mol Biol Cell 27:608-16
Robert, Amélie; Hookway, Caroline; Gelfand, Vladimir I (2016) Intermediate filament dynamics: What we can see now and why it matters. Bioessays 38:232-43
Lin, Ni-Hsuan; Huang, Yu-Shan; Opal, Puneet et al. (2016) The role of gigaxonin in the degradation of the glial-specific intermediate filament protein GFAP. Mol Biol Cell 27:3980-3990

Showing the most recent 10 out of 44 publications