The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior

Venturini, Valeria; Pezzano, Fabio; Català-Castro, Frederic; Häkkinen, Hanna-Maria; Jiménez‐Delgado, Senda; Colomer-Rosell, Mariona; Marro, Mónica; Tolosa-Ramon, Queralt; Paz-López, Sonia; Valverde, Miguel A.; Weghuber, Julian; Loza-Álvarez, Pablo; Krieg, Michael; Wieser, Stefan; Ruprecht, Verena

doi:10.1126/science.aba2644

Cited by 267 publications

(328 citation statements)

References 85 publications

(70 reference statements)

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“…The relatively large and incompressible nucleus restricts migration through small openings and thus movement through tortuous environments requires the ability to either sense pore size and find routes with larger pores (Lomakin et al, 2020;Renkawitz et al, 2019) or deform the nucleus to squeeze through existing pores (Denais et al, 2016). Compression of the nucleus itself can even modulate cell migration mode (Venturini et al, 2020). A common theme in all these studies is the interaction of cells with materials that are sufficiently stiff to resist pushing or pulling or cause deformation of the nucleus.…”

Section: Introductionmentioning

confidence: 99%

Proteolysis-free cell migration through crowded environments via mechanical worrying

Welf

Driscoll

Sapoznik

et al. 2020

Preprint

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Migratory cells employ numerous strategies to navigate the very diverse 3D microenvironments found in vivo. These strategies are subdivided into those that create space by pericellular proteolysis of extracellular matrix (ECM) proteins and those that navigate existing spaces. We find that cells can employ an alternative mechanism by digging tunnels through 3D collagen networks without extracellular proteolysis. This is accomplished by persistent polarization of large dynamic membrane blebs at the closed end of the tunnel that repeatedly agitate the collagen, a process we termed mechanical worrying. We find that this agitation promotes breakage and internalization of collagen at the cell front along with extracellular fluid in a macropinocytosis-driven manner. Membrane blebs are short-lived relative to the timescale of migration, and thus their polarization is critical for persistent ablation of the ECM. We find that sustained interactions between the collagen at the cell front and small but persistent cortical adhesions induce PI-3 Kinase (PI3K) signaling that drives polarized bleb enlargement via the Rac1 – Arp2/3 pathway. This defines a mechanism for the reinforcement of bleb expansion against load, which enables precise ablation of mechanically unrestrained environments, such as those encountered in very compliant tissue.

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Section: Introductionmentioning

confidence: 99%

Proteolysis-free cell migration through crowded environments via mechanical worrying

Welf

Driscoll

Sapoznik

et al. 2020

Preprint

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“…Additionally, with the upregulation of vimentin, there is more mechanical cross-talk between the two cortices to perhaps increase the role of the nucleus itself in regulating cell mechanics. Recent work suggests that compressed nuclei release calcium into the cytoplasm to help reconfigure the cytoskeleton [87,88]. Therefore, our theoretical findings provide a much richer interpretation of how vimentin affects cell migration with the combination of stress coupler between inner and outer parts of the cell, nuclear protector, and now polarity regulator.…”

Section: Discussionmentioning

confidence: 69%

The role of vimentin-nuclear interactions in persistent cell motility through confined spaces

Gupta

Patteson

Schwarz

2021

Preprint

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The ability of cells to move through small spaces depends on the mechanical properties of the cellular cytoskeleton and on nuclear deformability. In mammalian cells, the cytoskeleton is comprised of three interacting, semi-flexible polymer networks: actin, microtubules, and intermediate filaments (IF). Recent experiments of mouse embryonic fibroblasts with and without vimentin have shown that the IF vimentin plays a role in confined cell motility. We, therefore, develop a minimal model of cells moving through confined geometries that effectively includes all three types of cytoskeletal filaments with a cell consisting of an actomyosin cortex and a deformable cell nucleus and mechanical connections between the two cortices---the outer actomyosin one and the inner nuclear one. By decreasing the amount of vimentin, we find that the cell speed is typically faster for vimentin-null cells as compared to cells with vimentin. Vimentin-null cells also contain more deformed nuclei in confinement. Finally, vimentin affects nucleus positioning within the cell. By positing that as the nucleus position deviates further from the center of mass of the cell, microtubules become more oriented in a particular direction to enhance cell persistence or polarity, we show that vimentin-nulls are more persistent than vimentin-full cells. The enhanced persistence indicates that the vimentin-null cells are more subjugated by the confinement since their internal polarization mechanism that depends on cross-talk of the centrosome with the nucleus and other cytoskeletal connections is diminished. In other words, the vimentin-null cells rely more heavily on external cues. Our modeling results present a quantitative interpretation for recent experiments and have implications for understanding the role of vimentin in the epithelial-mesenchymal transition.

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“…Tissue damage activates cPLA2, triggering arachidonic acid release, which, in turn, is oxidized to pro-inflammatory eicosanoids by the 5-LOX at the NE (Enyedi et al, 2016). Studies performed both in vivo and in vitro showed that upon NE stretching and swelling, i.e., increased tension, the nucleoplasmic inactive portion of cPLA2 translocates to the inner NE where it triggers arachidonic acid release (Enyedi et al, 2016;Jiménez-delgado et al, 2020;Lomakin et al, 2020). This event is partially due to increased Ca 2+ levels in the cytoplasm.…”

Section: Activation Of Cytoplasmic Phospholipase A2 (Cpla2)mentioning

confidence: 99%

“…Interestingly, the nucleus is emerging as a fundamental player for cellular mechanosensing, and its capability to deform and properly react to external mechanical cues is probably strictly related to the functionality of its loadbearing elements (Navarro et al, 2016). Recent publications pointed out that the nucleus tensional state is a sensor of both cellular compression and stretching (Jiménez-delgado et al, 2020;Lomakin et al, 2020). In fact, when a cell is spatially constrained, the extent of nuclear deformation and the consequent stretching of the NE trigger remodeling of actomyosin cortex finally leading to increased cellular contractility (Lomakin et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Tailoring Cellular Function: The Contribution of the Nucleus in Mechanotransduction

Pennacchio

Nastały

Poli

et al. 2021

Front. Bioeng. Biotechnol.

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Cells sense a variety of different mechanochemical stimuli and promptly react to such signals by reshaping their morphology and adapting their structural organization and tensional state. Cell reactions to mechanical stimuli arising from the local microenvironment, mechanotransduction, play a crucial role in many cellular functions in both physiological and pathological conditions. To decipher this complex process, several studies have been undertaken to develop engineered materials and devices as tools to properly control cell mechanical state and evaluate cellular responses. Recent reports highlight how the nucleus serves as an important mechanosensor organelle and governs cell mechanoresponse. In this review, we will introduce the basic mechanisms linking cytoskeleton organization to the nucleus and how this reacts to mechanical properties of the cell microenvironment. We will also discuss how perturbations of nucleus–cytoskeleton connections, affecting mechanotransduction, influence health and disease. Moreover, we will present some of the main technological tools used to characterize and perturb the nuclear mechanical state.

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The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior

Cited by 267 publications

References 85 publications

Proteolysis-free cell migration through crowded environments via mechanical worrying

Proteolysis-free cell migration through crowded environments via mechanical worrying

The role of vimentin-nuclear interactions in persistent cell motility through confined spaces

Tailoring Cellular Function: The Contribution of the Nucleus in Mechanotransduction

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