Modeling of Mechanosensing Mechanisms Reveals Distinct Cell Migration Modes to Emerge From Combinations of Substrate Stiffness and Adhesion Receptor–Ligand Affinity

Vargas, Diego A.; Gonçalves, Inês G.; Heck, Tommy; Smeets, Bart; Lafuente-Gracia, Laura; Ramón, Herman; Oosterwyck, Hans Van

doi:10.3389/fbioe.2020.00459

Cited by 12 publications

(8 citation statements)

References 59 publications

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“…Biophysical properties including stiffness, porosity, density, and surface topology [12,[19][20][21][22] have all been implicated in cellular signals that trigger migratory capacity. Furthermore, an intrinsic cell state, such as the degree of differentiation, may be fine-tuned by differential mechanosensing thresholds, which contribute to tumor metastasis and growth [23][24][25]. This concept is close to a general observation that the higher stiffness of ECM is prone to the development of cancer metastasis [23,[26][27][28][29][30].…”

Section: Introductionmentioning

confidence: 66%

“…Furthermore, an intrinsic cell state, such as the degree of differentiation, may be fine-tuned by differential mechanosensing thresholds, which contribute to tumor metastasis and growth [23][24][25]. This concept is close to a general observation that the higher stiffness of ECM is prone to the development of cancer metastasis [23,[26][27][28][29][30]. It is also known that cancer is a stem cell-based disease.…”

Section: Introductionmentioning

confidence: 74%

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Physical Cues in the Microenvironment Regulate Stemness-Dependent Homing of Breast Cancer Cells

Chu

Chen

Hsu

et al. 2020

Cancers

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Tissue-specific microenvironmental factors contribute to the targeting preferences of metastatic cancers. However, the physical attributes of the premetastatic microenvironment are not yet fully characterized. In this research, we develop a transwell-based alginate hydrogel (TAH) model to study how permeability, stiffness, and roughness of a hanging alginate hydrogel regulate breast cancer cell homing. In this model, a layer of physically characterized alginate hydrogel is formed at the bottom of a transwell insert, which is placed into a matching culture well with an adherent monolayer of breast cancer cells. We found that breast cancer cells dissociate from the monolayer and home to the TAH for continual growth. The process is facilitated by the presence of rich serum in the upper chamber, the increased stiffness of the gel, as well as its surface roughness. This model is able to support the homing ability of MCF-7 and MDA-MB-231 cells drifting across the vertical distance in the culture medium. Cells homing to the TAH display stemness phenotype morphologically and biochemically. Taken together, these findings suggest that permeability, stiffness, and roughness are important physical factors to regulate breast cancer homing to a premetastatic microenvironment.

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Section: Introductionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 74%

Physical Cues in the Microenvironment Regulate Stemness-Dependent Homing of Breast Cancer Cells

Chu

Chen

Hsu

et al. 2020

Cancers

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“…Overall, the model presented here is an extension of, or borrows from, a number of prior actin-myosin force generation and filament sliding models [51,57,95]. It also borrows from other traction force, actin-integrin-substrate adhesion models [13,36,96]. Specific features new to this model are-1) The model describes five stages to allow for myosin activation via phosphorylation, as compared to the one [51].…”

Section: Discussionmentioning

confidence: 99%

“…Substrate stiffness has been shown to be an important parameter in cellular force generation. Stiffer substrates increase traction force [10][11][12][13]. Substrate stiffness also regulates the degree of cell-substrate adhesion and the size of the adhesion complex [14,15].…”

Section: Introductionmentioning

confidence: 99%

Chemo-Mechanical Factors That Limit Cellular Force Generation

et al. 2022

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Cellular traction forces that are dependent on actin-myosin activity are necessary for numerous developmental and physiological processes. As traction force emerges as a promising cancer biomarker there is a growing need to understand force generation in response to chemical and mechanical cues. Our goal is to present a unified modeling framework that integrates actin-myosin activity, substrate stiffness, integrin bond type, and adhesion complex dynamics to explain how force develops under specific conditions. Our simulation results show that substrate stiffness and number of myosin motors contribute to the maximum actin-myosin forces that can be generated but do not solely control the force transmitted by the cells to the surface, i.e., the traction force. The kinetics of the bonds between the cell and the substrate plays an equally important role. Overall, we find that while the cell can generate large actin-myosin forces in individual stress fibers (> 300 pN), the maximum force transmitted to the surface per cell-substrate attachment only reaches a fraction of these values (approx. 50 pN). Traction stress, the sum of forces transferred by all cell-substrate attachments in a unit area, is biphasic or sigmoidal with increasing substrate stiffness depending on the number of active myosin motors generating forces. Finally, we conclude that adhesions < 1 μm2 generate widely variable traction forces and that impulse, the magnitude and duration of a force generating event, is a key limiting factor in traction stress.

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“…[43][44][45][46][47] Keratocytes also exhibit durotaxis and mechanosensing, i.e., the migration to stiffer regions of materials. [48,49] Alteration in ECM stiffness can change, for instance, actin stress fiber production and focal adhesions, as well as alter keratocytes' phenotype. [50,60] Significant differences in keratocyte alignment, morphology and matrix reorganization are observed between anisotropic and isotropic environments.…”

Section: Mechanical Characteristics Of the Corneal Stroma And The Impact On Corneal Keratocytesmentioning

confidence: 99%

Mechanical Properties of Bioengineered Corneal Stroma

Formisano

Putten

Grant

et al. 2021

Adv Healthcare Materials

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For the majority of patients with severe corneal injury or disease, corneal transplantation is the only suitable treatment option. Unfortunately, the demand for donor corneas greatly exceeds the availability. To overcome shortage issues, a myriad of bioengineered constructs have been developed as mimetics of the corneal stroma over the last few decades. Despite the sheer number of bioengineered stromas developed , these implants fail clinical trials exhibiting poor tissue integration and adverse effects in vivo. Such shortcomings can partially be ascribed to poor biomechanical performance. In this review, existing approaches for bioengineering corneal stromal constructs and their mechanical properties are described. The information collected in this review can be used to critically analyze the biomechanical properties of future stromal constructs, which are often overlooked, but can determine the failure or success of corresponding implants.

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Modeling of Mechanosensing Mechanisms Reveals Distinct Cell Migration Modes to Emerge From Combinations of Substrate Stiffness and Adhesion Receptor–Ligand Affinity

Cited by 12 publications

References 59 publications

Physical Cues in the Microenvironment Regulate Stemness-Dependent Homing of Breast Cancer Cells

Physical Cues in the Microenvironment Regulate Stemness-Dependent Homing of Breast Cancer Cells

Chemo-Mechanical Factors That Limit Cellular Force Generation

Mechanical Properties of Bioengineered Corneal Stroma

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