Mitotic Rounding Alters Cell Geometry to Ensure Efficient Bipolar Spindle Formation

Lancaster, Oscar M.; Berre, Maël Le; Dimitracopoulos, Andrea; Bonazzi, Daria; Zlotek-Zlotkiewicz, Ewa; Picone, Remigio; Duke, Thomas; Piel, Matthieu; Baum, Buzz

doi:10.1016/j.devcel.2013.03.014

Cited by 276 publications

(361 citation statements)

References 67 publications

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“…When applied forces were increased to 150 and 200 nN, confined cells were unable to rise above 7 μm, concomitant with even more drastic distortion of spindle morphology, persistent stray chromosomes, and failure of cells to initiate chromosome segregation within 120 min. In accordance with these results, Lancaster et al also identified ∼7 μm as the critical height that causes severe spindle assembly defects and delay in mitotic progression via an inability to satisfy the spindle assembly checkpoint in HeLa cells (2). Thus, we determined that single mitotic HeLa cells could withstand confinement forces up to 100 nN before succumbing to heights that retard mitotic progression due to spindle dysfunction.…”

Section: Significancesupporting

confidence: 83%

“…In mitosis, cells round up and reduce adhesion to extracellular matrix or substrate (1)(2)(3). When attempting to confine cells with a tilted AFM cantilever, cells easily slide away (18).…”

Section: Resultsmentioning

confidence: 99%

“…In mitosis, cells generate actomyosindependent (1) intracellular pressure to round up and optimize geometry for proper function of the mitotic spindle, the machinery that organizes and segregates chromosomes (2,9,10,22). Restricting cell rounding height below 5-8 μm with microfabricated PDMS chambers perturbs mitotic progression in several cell types (2, 10), but the forces that cells can withstand remain unquantified.…”

Section: Significancementioning

confidence: 99%

“…Thus, we reveal how the mechanical properties of mitotic cells and their response to external forces are linked to mitotic progression under conditions of mechanical confinement. I n mitosis, eukaryotic cells down-regulate focal adhesions and increase their cortical tension and intracellular pressure, thereby generating force to round up against external impediments (1)(2)(3). Recent studies in the epithelium and epidermis of various organisms indicate that mitotic cell rounding is involved in tissue organization, development, and homeostasis (4)(5)(6)(7)(8).…”

mentioning

confidence: 99%

“…Despite the importance of cell rounding in mitotic progression and tissue organization, the mechanical robustness of mitotic cells remains poorly investigated even in vitro, probably due to a paucity of suitable experimental tools that can apply precise forces to poorly adherent cells. Confining cell rounding below 5-8 μm with microfabricated polydimethylsiloxane (PDMS) chambers perturbs mitotic progression in several cell types (2,10), but the forces required to do this remain unquantified. Thus, the magnitude of confinement force required to prevent mitosis and the mechanisms of cell response to such forces are not known.…”

mentioning

confidence: 99%

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Mechanical control of mitotic progression in single animal cells

Cattin

Düggelin

Martínez-Martín

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Despite the importance of mitotic cell rounding in tissue development and cell proliferation, there remains a paucity of approaches to investigate the mechanical robustness of cell rounding. Here we introduce ion beam-sculpted microcantilevers that enable precise force-feedback-controlled confinement of single cells while characterizing their progression through mitosis. We identify three force regimes according to the cell response: small forces (∼5 nN) that accelerate mitotic progression, intermediate forces where cells resist confinement (50-100 nN), and yield forces (>100 nN) where a significant decline in cell height impinges on microtubule spindle function, thereby inhibiting mitotic progression. Yield forces are coincident with a nonlinear drop in cell height potentiated by persistent blebbing and loss of cortical F-actin homogeneity. Our results suggest that a buildup of actomyosin-dependent cortical tension and intracellular pressure precedes mechanical failure, or herniation, of the cell cortex at the yield force. Thus, we reveal how the mechanical properties of mitotic cells and their response to external forces are linked to mitotic progression under conditions of mechanical confinement.

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Section: Significancesupporting

confidence: 83%

“…In mitosis, cells round up and reduce adhesion to extracellular matrix or substrate (1)(2)(3). When attempting to confine cells with a tilted AFM cantilever, cells easily slide away (18).…”

Section: Resultsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Mechanical control of mitotic progression in single animal cells

Cattin

Düggelin

Martínez-Martín

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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3D Confinement Regulates Cell Life and Death

Dudaryeva

Bucciarelli

Bovone

et al. 2021

Adv Funct Materials

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Biophysical properties of the cellular microenvironment, including stiffness and geometry, have been shown to influence cell function. Recent findings have implicated 3D confinement as an important regulator of cell behavior. The understanding of how mechanical signals direct cell function is based primarily on 2D studies. To investigate how the extent of 3D confinement affects cell function, a single cell culture platform is fabricated with geometrically defined and fully enclosed microwells and it is applied to investigate how niche volume and stiffness affect human mesenchymal stem cells (hMSC) life and death. The viability and proliferation of hMSCs in confined 3D microniches are compared with unconfined cells in 2D. Confinement biases hMSC viability and proliferation, and this influence depends on the niche volume and stiffness. The rate of cell death increases and proliferation markedly decreases upon 3D confinement. The observed differences in hMSC behavior are correlated to changes in nuclear morphology and YES-associated protein (YAP) localization. In smaller 3D microniches, hMSCs display smaller and more rounded nuclei and primarily cytoplasmic YAP localization, indicating reduced mechanical activation upon confinement. Interestingly, these effects scale with the extent of 3D confinement. These results demonstrate that the extent of confinement in 3D can be an important regulator of cell function.

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Intracellular Mechanical Drugs Induce Cell‐Cycle Altering and Cell Death

et al. 2022

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physical terms, the combination of cell membrane-cortex system and cytoskeleton constitutes a mechanical system whose stability is based on a force balance between compression and tensileload-bearing components. [1] Any physical perturbation of this cellular mechanical system elicits a redistribution of forces and rearrangement of mechanical elements that can be disruptive. [3] Thus, it is not surprising that multiple chemical drugs for research and therapeutics target to alter the cellular mechanical performance. Anticancer drugs such as paclitaxel or colchicine affect the microtubules, provoking mitotic catastrophe to cause cell death. [4,5] Other compounds, including cytochalasin B, cytochalasin D, and latrunculin A disrupt actin filaments, also disturbing cell function and growth. [6] Intracellular mechanical cues induced by physiological internalization of large objects can also alter the redistribution of forces and the rearrangement of mechanical elements. Indeed, during entosis (the engulfment of one living cell by another), cytokinesis in the engulfing cell is perturbed, which can cause aneuploidy. [7,8] This has parallels to cell division perturbation when cells are exposed to natural or artificial "long" fibrous material such as asbestos fibers that can induce genomic changes and cancer by sterically blocking cytokinesis. [9] Current advances in materials science have demonstrated that extracellular mechanical cues can define cell function and cell fate. However, a fundamental understanding of the manner in which intracellular mechanical cues affect cell mechanics remains elusive. How intracellular mechanical hindrance, reinforcement, and supports interfere with the cell cycle and promote cell death is described here. Reproducible devices with highly controlled size, shape, and with a broad range of stiffness are internalized in HeLa cells. Once inside, they induce characteristic cell-cycle deviations and promote cell death. Device shape and stiffness are the dominant determinants of mechanical impairment. Device structural support to the cell membrane and centering during mitosis maximize their effects, preventing spindle centering, and correct chromosome alignment. Nanodevices reveal that the spindle generates forces larger than 114 nN which overcomes intracellular confinement by relocating the device to a less damaging position. By using intracellular mechanical drugs, this work provides a foundation to defining the role of intracellular constraints on cell function and fate, with relevance to fundamental cell mechanics and nanomedicine.

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Mitotic Rounding Alters Cell Geometry to Ensure Efficient Bipolar Spindle Formation

Cited by 276 publications

References 67 publications

Mechanical control of mitotic progression in single animal cells

Mechanical control of mitotic progression in single animal cells

3D Confinement Regulates Cell Life and Death

Intracellular Mechanical Drugs Induce Cell‐Cycle Altering and Cell Death

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