More Like this

1. Understanding cytoskeletal avalanches using mechanical stability analysis

   Floyd, Carlos; Levine, Herbert; Jarzynski, Christopher; Papoian, Garegin A. (June 2020, ArXivorg)

   null (Ed.)

   Eukaryotic cells are mechanically supported by a polymer network called the cytoskeleton, which consumes chemical energy to dynamically remodel its structure. Recent experiments in vivo have revealed that this remodeling occasionally happens through anomalously large displacements, reminiscent of earthquakes or avalanches. These cytoskeletal avalanches might indicate that the cytoskeleton's structural response to a changing cellular environment is highly sensitive, and they are therefore of significant biological interest. However, the physics underlying "cytoquakes" is poorly understood. Here, we use agent-based simulations of cytoskeletal self-organization to study fluctuations in the network's mechanical energy. We robustly observe non-Gaussian statistics and asymmetrically large rates of energy release compared to accumulation in a minimal cytoskeletal model. The large events of energy release are found to correlate with large, collective displacements of the cytoskeletal filaments. We also find that the changes in the localization of tension and the projections of the network motion onto the vibrational normal modes are asymmetrically distributed for energy release and accumulation. These results imply an avalanche-like process of slow energy storage punctuated by fast, large events of energy release involving a collective network rearrangement. We further show that mechanical instability precedes cytoquake occurrence through a machine learning model that dynamically forecasts cytoquakes using the vibrational spectrum as input. Our results provide the first connection between the cytoquake phenomenon and the network's mechanical energy and can help guide future investigations of the cytoskeleton's structural susceptibility. 

   more » « less
2. Lévy-distributed fluctuations in the living cell cortex

   https://doi.org/10.1103/PhysRevResearch.6.043265  

   Sivarajan, Shankar; Shi, Yu; Xiang, Katherine M; Rodríguez-Cruz, Clary; Porter, Christopher L; Kostecki, Geran M; Tung, Leslie; Crocker, John C; Reich, Daniel H (December 2024, Physical Review Research)

   The actomyosin cortex is an active material that provides animal cells with a strong but flexible exterior whose mechanics, including non-Gaussian fluctuations and occasional large displacements or cytoquakes, have defied explanation. We study the active fluctuations of the cortex using nanoscale tracking of arrays of flexible microposts adhered to multiple cultured cell types. When the confounding effects of static heterogeneity and tracking error are removed, the fluctuations are found to be heavy tailed and well described by a truncated Lévy $\alpha$-stable distribution over a wide range of timescales, in multiple cell types. The largest random displacements closely resemble the earlier-reported cytoquakes, but notably, we find these cytoquakes are not due to earthquakelike cooperative rearrangement of many cytoskeletal elements. Rather, they are indistinguishable from chance large excursions of a superdiffusive random process driven by heavy-tailed noise. The noncooperative microscopic events driving these fluctuations need not be larger than the expected elastic energy of single tensed cortical actin filaments, and the implied distribution of microscopic event energies will need to be accounted for by future models of the cytoskeleton. 

   more » « less
3. The role of the Arp2/3 complex in shaping the dynamics and structures of branched actomyosin networks

   https://doi.org/10.1073/pnas.1922494117  

   Liman, James; Bueno, Carlos; Eliaz, Yossi; Schafer, Nicholas P.; Waxham, M. Neal; Wolynes, Peter G.; Levine, Herbert; Cheung, Margaret S. (April 2020, Proceedings of the National Academy of Sciences)

   Actomyosin networks give cells the ability to move and divide. These networks contract and expand while being driven by active energy-consuming processes such as motor protein walking and actin polymerization. Actin dynamics is also regulated by actin-binding proteins, such as the actin-related protein 2/3 (Arp2/3) complex. This complex generates branched filaments, thereby changing the overall organization of the network. In this work, the spatiotemporal patterns of dynamical actin assembly accompanying the branching-induced reorganization caused by Arp2/3 were studied using a computational model (mechanochemical dynamics of active networks [MEDYAN]); this model simulates actomyosin network dynamics as a result of chemical reactions whose rates are modulated by rapid mechanical equilibration. We show that branched actomyosin networks relax significantly more slowly than do unbranched networks. Also, branched networks undergo rare convulsive movements, “avalanches,” that release strain in the network. These avalanches are associated with the more heterogeneous distribution of mechanically linked filaments displayed by branched networks. These far-from-equilibrium events arising from the marginal stability of growing actomyosin networks provide a possible mechanism of the “cytoquakes” recently seen in experiments. 

   more » « less
4. Pervasive cytoquakes in the actomyosin cortex across cell types and substrate stiffness

   https://doi.org/10.1093/intbio/zyab017  

   Shi, Yu; Sivarajan, Shankar; Xiang, Katherine M.; Kostecki, Geran M.; Tung, Leslie; Crocker, John C.; Reich, Daniel H. (December 2021, Integrative Biology)

   Abstract The actomyosin cytoskeleton enables cells to resist deformation, crawl, change their shape and sense their surroundings. Despite decades of study, how its molecular constituents can assemble together to form a network with the observed mechanics of cells remains poorly understood. Recently, it has been shown that the actomyosin cortex of quiescent cells can undergo frequent, abrupt reconfigurations and displacements, called cytoquakes. Notably, such fluctuations are not predicted by current physical models of actomyosin networks, and their prevalence across cell types and mechanical environments has not previously been studied. Using micropost array detectors, we have performed high-resolution measurements of the dynamic mechanical fluctuations of cells’ actomyosin cortex and stress fiber networks. This reveals cortical dynamics dominated by cytoquakes—intermittent events with a fat-tailed distribution of displacements, sometimes spanning microposts separated by 4 μm, in all cell types studied. These included 3T3 fibroblasts, where cytoquakes persisted over substrate stiffnesses spanning the tissue-relevant range of 4.3 kPa–17 kPa, and primary neonatal rat cardiac fibroblasts and myofibroblasts, human embryonic kidney cells and human bone osteosarcoma epithelial (U2OS) cells, where cytoquakes were observed on substrates in the same stiffness range. Overall, these findings suggest that the cortex self-organizes into a marginally stable mechanical state whose physics may contribute to cell mechanical properties, active behavior and mechanosensing. 

   more » « less
5. Active gels, heavy tails, and the cytoskeleton

   https://doi.org/10.1039/D1SM00705J  

   Swartz, Daniel W.; Camley, Brian A. (November 2021, Soft Matter)

   The eukaryotic cell's cytoskeleton is a prototypical example of an active material: objects embedded within it are driven by molecular motors acting on the cytoskeleton, leading to anomalous diffusive behavior. Experiments tracking the behavior of cell-attached objects have observed anomalous diffusion with a distribution of displacements that is non-Gaussian, with heavy tails. This has been attributed to “cytoquakes” or other spatially extended collective effects. We show, using simulations and analytical theory, that a simple continuum active gel model driven by fluctuating force dipoles naturally creates heavy power-law tails in cytoskeletal displacements. We predict that this power law exponent should depend on the geometry and dimensionality of where force dipoles are distributed through the cell; we find qualitatively different results for force dipoles in a 3D cytoskeleton and a quasi-two-dimensional cortex. We then discuss potential applications of this model both in cells and in synthetic active gels. 

   more » « less