The laminin–keratin link shields the nucleus from mechanical deformation and signalling

Kechagia, Zanetta; Sáez, Pablo; Gómez-González, Manuel; Canales, Brenda; Viswanadha, Srivatsava; Zamarbide, Martín; Andreu, Ion; Koorman, Thijs; Beedle, Amy E. M.; Elosegui-Artola, Alberto; Derksen, Patrick W. B.; Trepat, Xavier; Arroyo, Marino; Roca-Cusachs, Pere

doi:10.1038/s41563-023-01657-3

Cited by 32 publications

(24 citation statements)

References 76 publications

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“…The difference from our observations is likely due to our gel's high protein binding capacity(~2.2 times of glass surface), which results in a dense ECM ligand (Fig. 1G-H), thus promoting nuclear YAP, as observed previously (Kechagia et al, 2023;Lee et al, 2019;Stanton et al, 2019).…”

Section: Synthesis and Characterization Of Photocurable Pva-methacryl...contrasting

confidence: 79%

Spatial cell fate manipulation of human pluripotent stem cells by controlling the microenvironment using photocurable hydrogel

Wang

Numada

Wagai

et al. 2022

Preprint

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Human pluripotent stem cells(hPSCs) sense the surrounding chemical, and physical microenvironment and adjust their behaviors accordingly. However, current in vitro research is mostly conducted in plastic culture wares which provides an oversimplified microenvironment compared with in vivo. Recently, increasing evidence has shown that the physical microenvironment plays a critical role in hPSCs differentiation and maintenance. However, current studies were conducted by a bulk culture of hPSCs on substrates with different stiffness. The development of biocompatible materials that allow spatial control of the chemical and mechanical environment for human PSC culture has not yet been achieved. Culture substrates allowing flexible manipulation of physical properties spatially would help us better recapitulate the in vivo environment, and benefit tissue engineering. In this study, we developed a photocurable hydrogel (PVA-PEG gel) which allows us to spatially control the stiffness and the structure at the micrometre level. The generated hydrogel can be functionalized using different ECM proteins. Laminin 511 functionalized PVA-PEG gel supports hPSCs growth and differentiation. Furthermore, by spatially controlling the stiffness of the patterned gel, we could selectively differentiate cells on the same patterned gel, generating complex patterned structures.

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Section: Synthesis and Characterization Of Photocurable Pva-methacryl...contrasting

confidence: 79%

Spatial cell fate manipulation of human pluripotent stem cells by controlling the microenvironment using photocurable hydrogel

Wang

Numada

Wagai

et al. 2022

Preprint

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“…Of note, we combined both drugs because, in an epithelial context, Para-NitroBlebbistatin alone is not sufficient to deplete nuclear mechanotransduction. Indeed, myosin contractility inhibition alone can lead to increased cell spreading and nuclear deformation, increasing (rather than decreasing) YAP nuclear concentration (Kechagia et al, 2023).…”

Section: Resultsmentioning

confidence: 99%

Nucleocytoplasmic transport senses mechanics independently of cell density in cell monolayers

Granero-Moya,

Belthier,

Groenen

et al. 2024

Preprint

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Cells sense and respond to mechanical forces through mechanotransduction, which regulates processes in health and disease. In single cells, mechanotransduction involves the transmission of force to the cell nucleus, where it affects nucleocytoplasmic transport (NCT) and the subsequent nuclear localization of transcriptional regulators such as YAP. However, if and how NCT is mechanosensitive in multicellular systems is unclear. Here, we characterize and use a fluorescent sensor of nucleocytoplasmic transport (Sencyt) and demonstrate that nucleocytoplasmic transport responds to mechanics but not cell density in cell monolayers. Using monolayers of both epithelial and mesenchymal phenotype, we show that NCT is altered in response both to osmotic shocks, and to the inhibition of cell contractility. Further, NCT correlates with the degree of nuclear deformation measured through nuclear solidity, a shape parameter related to nuclear envelope tension. In contrast and in opposition to YAP, NCT is not affected by cell density, showing that the response of YAP to both mechanics and cell-cell contacts operates through distinct mechanisms. Our results demonstrate the generality of the mechanical regulation of NCT.

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“…The formation of hemidesmosomes has been shown to reduce cellular traction forces 48 and sensitivity of nuclear mechanotransduction 49 via their role in nucleation and organization of the keratin cytoskeleton 49,50 . Encouraged by our in vitro findings, we were curious whether the different laminin densities in Bruch’s membrane coincided with different organisation of the keratin network in RPE.…”

Section: Resultsmentioning

confidence: 99%

“…More recently, data from different labs have demonstrated that hemidesmosomes and the keratin network reduce cellular traction force 48 and protect the nucleus from mechanical strain 49 . In agreement with the tensegrity model, cellular mechanics is a balance of cytoskeleton-driven forces, where a contractile actin cytoskeleton is counterbalanced by intermediate filaments [58][59][60] .…”

Section: Discussionmentioning

confidence: 99%

“…The role of hemidesmosomes in organizing the keratin network is crucial for the mechanical integrity of epithelial tissues 56,57 and was proposed to define their textile nature 44 . More recently, data from different labs demonstrated that hemidesmosomes and the keratin network reduce cellular traction force 48 and protect the nucleus from mechanical strain 49 . In agreement with the tensegrity model, cellular mechanics is a balance of cytoskeleton-driven forces, where a contractile actin cytoskeleton is counterbalanced by intermediate filaments [58][59][60] .…”

Section: Discussionmentioning

confidence: 99%

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Laminin-defined Mechanical Status Modulates Retinal Pigment Epithelium Functionality

Kozyrina

Piskova

Doolaar

et al. 2023

Preprint

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Epithelial cells are highly interconnected, whereby they acquire mesoscale mechanical properties to accomplish specific tissue functions. In homeostasis, these mechanical features can be summarised as mechanical homeostasis, regulated by the balance of intercellular tension and extracellular matrix adhesion forces. In the outer retina, the significance of these forces in defining its mechanical homeostasis and vision remains poorly understood. The retinal pigmented epithelium (RPE) is located at the base of the retina and supports vision by ensuring the light sensitivity and lifespan of photoreceptor cells. Due to different photoreceptor densities, this functional demand on the RPE varies from the most illuminated macula to the less illuminated retinal periphery and corresponds to a significant difference in monolayer organisation. In this work, we hypothesised that extracellular matrix cues define the relation between RPE organisation, mechanical status and functional demand. We found that the density of basement membrane laminin alpha 5 modulates RPE contractility levels which directly control the epithelium efficiency in phagocyting photoreceptor outer segments. In vivo, laminin alpha 5 density gradient follows retinal functional demand, thus supporting the physiological role of laminin alpha 5 in controlling RPE mechanical homeostasis. ECM-defined mechanical status of the RPE provides a novel parameter to consider for visual function and opens new paths of investigation for sight-threatening diseases such as high myopia and age-related macular degeneration.

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The laminin–keratin link shields the nucleus from mechanical deformation and signalling

Cited by 32 publications

References 76 publications

Spatial cell fate manipulation of human pluripotent stem cells by controlling the microenvironment using photocurable hydrogel

Spatial cell fate manipulation of human pluripotent stem cells by controlling the microenvironment using photocurable hydrogel

Nucleocytoplasmic transport senses mechanics independently of cell density in cell monolayers

Laminin-defined Mechanical Status Modulates Retinal Pigment Epithelium Functionality

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