Nuclear mechanics during and after constricted migration

2019 ◽  
Vol 35 (2) ◽  
pp. 299-308 ◽  
Author(s):  
Yuntao Xia ◽  
Charlotte R. Pfeifer ◽  
Dennis E. Discher
Keyword(s):  
Nuclear Mechanics

The Role of Nuclear Stiffness and Resilience in Mechanotransduction

2010 ◽  
Author(s):  
Kris Noel Dahl ◽  
Elizabeth A. Booth-Gauthier ◽  
Alexandre J. S. Ribeiro ◽  
Zhixia Zhong
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Live Cell Imaging ◽  
Volume Fraction ◽  
Direct Role ◽  
Intact Cells ◽  
Large Volume Fraction ◽  
Nuclear Mechanics ◽  
Model Cell

Mechanical force is found to be increasingly important during development and for proper homeostatic maintenance of cells and tissues. The nucleus occupies a large volume fraction of the cell and is interconnected with the cytoskeleton. Here, to determine the direct role of the nucleus itself in converting forces to changes in gene expression, also known as, mechanotransduction, we examine changes in nuclear mechanics and gene reorganization associated with cell fate and with extracellular force. We measure mechanics of nuclei in many model cell systems using micropipette aspiration to show changes in nuclear mechanics. In intact cells we characterize the rheological changes induced in the genome organization with live cell imaging and particle tracking, and we suggest how these changes relate to gene expression.

scholarly journals Mechanical phenotyping of acute promyelocytic leukemia reveals unique biomechanical responses in retinoic acid-resistant populations

2021 ◽  
Author(s):  
Brian Li ◽  
Annie Maslan ◽  
Aaron M Streets ◽  
Lydia L. Sohn
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Dna Content ◽  
Trichostatin A ◽  
Chromatin Condensation ◽  
Promyelocytic Leukemia ◽  
Mechanical Responses ◽  
Nuclear Mechanics ◽  
All Trans Retinoic Acid ◽  
M Phase

While all-trans retinoic acid (ATRA) is an essential therapy in the treatment of acute promyelocytic leukemia (APL), an aggressive subtype of acute myeloid leukemia, nearly 20% of APL patients are resistant to ATRA. As no biomarkers for ATRA resistance yet exist, we investigated whether cell mechanics could be associated with this pathological phenotype. Using mechano-node-pore sensing, a single-cell mechanical phenotyping platform, and patient-derived APL cell lines, NB4 (ATRA-sensitive) and AP-1060 (ATRA-resistant), we discovered that ATRA-resistant APL cells are less mechanically pliable. By investigating how different subcellular components of APL cells contribute to whole-cell mechanical phenotype, we determined that nuclear mechanics strongly influence APL cell mechanical responses. By arresting APL cells in S-phase or M-phase in the cell cycle, we found cell pliability to be inversely related to DNA content. In addition to DNA content affecting cell pliability, we observed that chromatin condensation also affects nuclear mechanics: decondensing chromatin with trichostatin A is especially effective in softening ATRA-resistant APL cells. RNA-Seq allowed us to compare the transcriptomic differences between ATRA-resistant and ATRA-responsive APL cells and highlighted gene expression changes that could be associated with mechanical changes. Overall, we demonstrate the potential of physical biomarkers in identifying APL resistance.

scholarly journals High-throughput microfluidic micropipette aspiration device to probe time-scale dependent nuclear mechanics in intact cells

Lab on a Chip ◽  
2019 ◽  
Vol 19 (21) ◽  
pp. 3652-3663 ◽  
Author(s):  
Patricia M. Davidson ◽  
Gregory R. Fedorchak ◽  
Solenne Mondésert-Deveraux ◽  
Emily S. Bell ◽  
Philipp Isermann ◽  
...  
Keyword(s):  
Image Analysis ◽  
High Throughput ◽  
Time Scale ◽  
Viscoelastic Properties ◽  
Micropipette Aspiration ◽  
Automated Image Analysis ◽  
Cell Nuclei ◽  
Intact Cells ◽  
Nuclear Mechanics ◽  
Analysis Platform

We report the development, validation, and application of an easy-to-use microfluidic micropipette aspiration device and automated image analysis platform that enables high-throughput measurements of the viscoelastic properties of cell nuclei.

scholarly journals WDR5 modulates cell motility and morphology and controls nuclear changes induced by a 3D environment

2018 ◽  
Vol 115 (34) ◽  
pp. 8581-8586 ◽  
Author(s):  
Pengbo Wang ◽  
Marcel Dreger ◽  
Elena Madrazo ◽  
Craig J. Williams ◽  
Rafael Samaniego ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Polarity ◽  
Underlying Mechanism ◽  
H3k4 Methylation ◽  
Nuclear Mechanics ◽  
3D Environment ◽  
3D Environments ◽  
And Migration

Cell migration through extracellular matrices requires nuclear deformation, which depends on nuclear stiffness. In turn, chromatin structure contributes to nuclear stiffness, but the mechanosensing pathways regulating chromatin during cell migration remain unclear. Here, we demonstrate that WD repeat domain 5 (WDR5), an essential component of H3K4 methyltransferase complexes, regulates cell polarity, nuclear deformability, and migration of lymphocytes in vitro and in vivo, independent of transcriptional activity, suggesting nongenomic functions for WDR5. Similarly, depletion of RbBP5 (another H3K4 methyltransferase subunit) promotes similar defects. We reveal that a 3D environment increases the H3K4 methylation dependent on WDR5 and results in a globally less compacted chromatin conformation. Further, using atomic force microscopy, nuclear particle tracking, and nuclear swelling experiments, we detect changes in nuclear mechanics that accompany the epigenetic changes induced in 3D conditions. Indeed, nuclei from cells in 3D environments were softer, and thereby more deformable, compared with cells in suspension or cultured in 2D conditions, again dependent on WDR5. Dissecting the underlying mechanism, we determined that actomyosin contractility, through the phosphorylation of myosin by MLCK (myosin light chain kinase), controls the interaction of WDR5 with other components of the methyltransferase complex, which in turn up-regulates H3K4 methylation activation in 3D conditions. Taken together, our findings reveal a nongenomic function for WDR5 in regulating H3K4 methylation induced by 3D environments, physical properties of the nucleus, cell polarity, and cell migratory capacity.

In Situ Hierarchical Strain Transfer From the Articular Cartilage Surface to the Chondrocyte Nucleus

2012 ◽  
Author(s):  
Jonathan T. Henderson ◽  
Corey P. Neu
Keyword(s):  
Extracellular Matrix ◽  
Articular Cartilage ◽  
Cartilage Surface ◽  
Strain Transfer ◽  
Nuclear Mechanics ◽  
Articular Cartilage Surface ◽  
Matrix Interactions ◽  
Wear And Tear ◽  
Extracellular Matrix Interactions

Osteoarthritis (OA) is a disabling disease, commonly thought of as the “wear and tear” of articular cartilage, afflicting 27 million Americans [1]. Multiple (e.g. biomechanical and biochemical) factors [2] contribute to maintenance of healthy joints through chondrocyte and extracellular matrix interactions. Interestingly, volumetric contractions of nuclei exhibit a zonal dependence [3], suggesting that nuclear mechanics may play a key role in the maintenance of healthy tissue by mechanically-mediated pathways.

scholarly journals Early Spindle Assembly in Drosophila Embryos: Role of a Force Balance Involving Cytoskeletal Dynamics and Nuclear Mechanics

2005 ◽  
Vol 16 (10) ◽  
pp. 4967-4981 ◽  
Author(s):  
E. N. Cytrynbaum ◽  
P. Sommi ◽  
I. Brust-Mascher ◽  
J. M. Scholey ◽  
A. Mogilner
Keyword(s):  
Spindle Assembly ◽  
Spindle Pole ◽  
Cortical Reorganization ◽  
Force Balance ◽  
Cell Cortex ◽  
Nuclear Dynamics ◽  
Nuclear Mechanics ◽  
Cytoskeletal Dynamics ◽  
Drosophila Embryos

Mitotic spindle morphogenesis depends upon the action of microtubules (MTs), motors and the cell cortex. Previously, we proposed that cortical- and MT-based motors acting alone can coordinate early spindle assembly in Drosophila embryos. Here, we tested this model using microscopy of living embryos to analyze spindle pole separation, cortical reorganization, and nuclear dynamics in interphase-prophase of cycles 11-13. We observe that actin caps remain flat as they expand and that furrows do not ingress. As centrosomes separate, they follow a linear trajectory, maintaining a constant pole-to-furrow distance while the nucleus progressively deforms along the elongating pole-pole axis. These observations are incorporated into a model in which outward forces generated by zones of active cortical dynein are balanced by inward forces produced by nuclear elasticity and during cycle 13, by Ncd, which localizes to interpolar MTs. Thus, the force-balance driving early spindle morphogenesis depends upon MT-based motors acting in concert with the cortex and nucleus.

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