Glass-like dynamics of collective cell migration Angelini, Thomas E; Hannezo, Edouard; Trepat, Xavier ...
Proceedings of the National Academy of Sciences - PNAS,
03/2011, Volume:
108, Issue:
12
Journal Article
Peer reviewed
Open access
Collective cell migration in tissues occurs throughout embryonic development, during wound healing, and in cancerous tumor invasion, yet most detailed knowledge of cell migration comes from ...single-cell studies. As single cells migrate, the shape of the cell body fluctuates dramatically through cyclic processes of extension, adhesion, and retraction, accompanied by erratic changes in migration direction. Within confluent cell layers, such subcellular motions must be coupled between neighbors, yet the influence of these subcellular motions on collective migration is not known. Here we study motion within a confluent epithelial cell sheet, simultaneously measuring collective migration and subcellular motions, covering a broad range of length scales, time scales, and cell densities. At large length scales and time scales collective migration slows as cell density rises, yet the fastest cells move in large, multicell groups whose scale grows with increasing cell density. This behavior has an intriguing analogy to dynamic heterogeneities found in particulate systems as they become more crowded and approach a glass transition. In addition we find a diminishing self-diffusivity of short-wavelength motions within the cell layer, and growing peaks in the vibrational density of states associated with cooperative cell-shape fluctuations. Both of these observations are also intriguingly reminiscent of a glass transition. Thus, these results provide a broad and suggestive analogy between cell motion within a confluent layer and the dynamics of supercooled colloidal and molecular fluids approaching a glass transition.
Cell nuclei rupture following exposure to mechanical force and/or upon weakening of nuclear integrity, but nuclear ruptures are repairable. Barrier-to-autointegration factor (BAF), a small ...DNA-binding protein, rapidly localizes to nuclear ruptures; however, its role at these rupture sites is unknown. Here, we show that it is predominantly a nonphosphorylated cytoplasmic population of BAF that binds nuclear DNA to rapidly and transiently localize to the sites of nuclear rupture, resulting in BAF accumulation in the nucleus. BAF subsequently recruits transmembrane LEM-domain proteins, causing their accumulation at rupture sites. Loss of BAF impairs recruitment of LEM-domain proteins and nuclear envelope membranes to nuclear rupture sites and prevents nuclear envelope barrier function restoration. Simultaneous depletion of multiple LEM-domain proteins similarly inhibits rupture repair. LEMD2 is required for recruitment of the ESCRT-III membrane repair machinery to ruptures; however, neither LEMD2 nor ESCRT-III is required to repair ruptures. These results reveal a new role for BAF in the response to and repair of nuclear ruptures.
Damage to the nervous system can result in loss of sensory and motor function, paralysis, or even death. To facilitate neural regeneration and functional recovery, researchers have employed ...biomaterials strategies to address both peripheral and central nervous system injuries. Injectable hydrogels that recapitulate native nerve extracellular matrix are especially promising for neural tissue engineering because they offer more flexibility for minimally invasive applications and provide a growth‐permissive substrate for neural cell types. Here, we explore the development of injectable hydrogels derived from decellularized rat peripheral nerves (referred to as “injectable peripheral nerve iPN hydrogels”), which are processed using a newly developed sodium deoxycholate and DNase (SDD) decellularization method. We assess the gelation kinetics, mechanical properties, cell bioactivity, and drug release kinetics of the iPN hydrogels. The iPN hydrogels thermally gel when exposed to 37°C in under 20 min and have mechanical properties similar to neural tissue. The hydrogels demonstrate in vitro biocompatibility through support of Schwann cell viability and metabolic activity. Additionally, iPN hydrogels promote greater astrocyte spreading compared to collagen I hydrogels. Finally, the iPN is a promising delivery vehicle of drug‐loaded microparticles for a combinatorial approach to neural injury therapies.
Cell Volume Fluctuations in MDCK Monolayers Zehnder, Steven M.; Suaris, Melanie; Bellaire, Madisonclaire M. ...
Biophysical journal,
01/2015, Volume:
108, Issue:
2
Journal Article
Peer reviewed
Open access
Cells moving collectively in tissues constitute a form of active matter, in which collective motion depends strongly on driven fluctuations at the single-cell scale. Fluctuations in cell area and ...number density are often seen in monolayers, yet their role in collective migration is not known. Here we study density fluctuations at the single- and multicell level, finding that single-cell volumes oscillate with a timescale of 4 h and an amplitude of 20%; the timescale and amplitude are found to depend on cytoskeletal activity. At the multicellular scale, density fluctuations violate the central limit theorem, highlighting the role of nonequilibrium driving forces in multicellular density fluctuations.
We report a photomediated disulfide cross-linking strategy for the generation of adaptable hydrogels from telechelic network precursors containing strained cyclic disulfides. Exploiting the intricate ...stereoelectronic properties of 1,2-dithiolanes arising from the unfavorable four-electron interaction in the disulfide scaffold, amphiphilic poly(ethylene glycol)-1,2-dithiolane conjugates formed free-standing adaptable hydrogels at 10 wt % polymer content upon disulfide photolysis under UV irradiation (λmax = 365 nm). Cross-linking was achieved in less than 10 min with tunable network moduli depending on irradiation time. Investigations into the gelation mechanism suggest the formation of free thiols during light exposure accounting for the dynamic nature of the gels. Furthermore, we successfully expanded this gelation strategy to green light (λmax = 515 nm) by employing the photosensitizer eosin Y, allowing for hydrogel formation open to air.
Bacterial biofilms are organized communities of cells living in association with surfaces. The hallmark of biofilm formation is the secretion of a polymeric matrix rich in sugars and proteins in the ...extracellular space. In Bacillus subtilis, secretion of the exopolysaccharide (EPS) component of the extracellular matrix is genetically coupled to the inhibition of flagella-mediated motility. The onset of this switch results in slow expansion of the biofilm on a substrate. Different strains have radically different capabilities in surface colonization: Flagella-null strains spread at the same rate as wild type, while both are dramatically faster than EPS mutants. Multiple functions have been attributed to the EPS, but none of these provides a physical mechanism for generating spreading. We propose that the secretion of EPS drives surface motility by generating osmotic pressure gradients in the extracellular space. A simple mathematical model based on the physics of polymer solutions shows quantitative agreement with experimental measurements of biofilm growth, thickening, and spreading. We discuss the implications of this osmotically driven type of surface motility for nutrient uptake that may elucidate the reduced fitness of the matrix-deficient mutant strains.
Writing in the granular gel medium Bhattacharjee, Tapomoy; Zehnder, Steven M; Rowe, Kyle G ...
Science advances,
09/2015, Volume:
1, Issue:
8
Journal Article
Peer reviewed
Open access
Gels made from soft microscale particles smoothly transition between the fluid and solid states, making them an ideal medium in which to create macroscopic structures with microscopic precision. ...While tracing out spatial paths with an injection tip, the granular gel fluidizes at the point of injection and then rapidly solidifies, trapping injected material in place. This physical approach to creating three-dimensional (3D) structures negates the effects of surface tension, gravity, and particle diffusion, allowing a limitless breadth of materials to be written. With this method, we used silicones, hydrogels, colloids, and living cells to create complex large aspect ratio 3D objects, thin closed shells, and hierarchically branched tubular networks. We crosslinked polymeric materials and removed them from the granular gel, whereas uncrosslinked particulate systems were left supported within the medium for long times. This approach can be immediately used in diverse areas, contributing to tissue engineering, flexible electronics, particle engineering, smart materials, and encapsulation technologies.
Natural killer (NK) cells are important effector cells in the immune response to cancer. Clinical trials on adoptively transferred NK cells in patients with solid tumors, however, have thus far been ...unsuccessful. As NK cells need to pass stringent safety evaluation tests before clinical use, the cells are cryopreserved to bridge the necessary evaluation time. Standard degranulation and chromium release cytotoxicity assays confirm the ability of cryopreserved NK cells to kill target cells. Here, we report that tumor cells embedded in a 3-dimensional collagen gel, however, are killed by cryopreserved NK cells at a 5.6-fold lower rate compared to fresh NK cells. This difference is mainly caused by a 6-fold decrease in the fraction of motile NK cells after cryopreservation. These findings may explain the persistent failure of NK cell therapy in patients with solid tumors and highlight the crucial role of a 3-D environment for testing NK cell function.
The recent attention given to functionalities that respond to mechanical force has led to a deeper understanding of force transduction and mechanical wear in polymeric materials. Furthermore, ...polymers have been carefully designed such that activation of "mechanophores" leads to productive outputs, such as material reinforcement or changes in optical properties. In this work, a crosslinker containing an anthracene-maleimide linkage was designed and used to prepare networks that display a fluorescence response when damaged. The pressure-dependent damage of poly(
N
,
N
-dimethylacrylamide) networks was monitored using solid-state fluorescence spectroscopy, with increasing compressive forces leading to higher degrees of mechanophore activation. When a stamp was used to compress the networks, only the areas in contact with the raised portion of the stamp underwent mechanophore activation, resulting in the generation of patterns that were only visible under UV light. Finally, an isomeric "flex" mechanophore was designed and used to prepare networks that were compressed and compared to the previously described networks.
The recent attention given to functionalities that respond to mechanical force has led to a deeper understanding of force transduction and mechanical wear in polymeric materials.
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