Dataset Information

Modeling the Mechanosensitivity of Neutrophils Passing through a Narrow Channel.

ABSTRACT: Recent experiments have found that neutrophils may be activated after passing through microfluidic channels and filters. Mechanical deformation causes disassembly of the cytoskeleton and a sudden drop of the elastic modulus of the neutrophil. This fluidization is followed by either activation of the neutrophil with protrusion of pseudopods or a uniform recovery of the cytoskeleton network with no pseudopod. The former occurs if the neutrophil traverses the narrow channel at a slower rate. We propose a chemo-mechanical model for the fluidization and activation processes. Fluidization is treated as mechanical destruction of the cytoskeleton by sufficiently rapid bending. Loss of the cytoskeleton removes a pathway by which cortical tension inhibits the Rac protein. As a result, Rac rises and polarizes through a wave-pinning mechanism if the chemical reaction rate is fast enough. This leads to recovery and reinforcement of the cytoskeleton at the front of the neutrophil, and hence protrusion and activation. Otherwise the Rac signal returns to a uniform pre-deformation state and no activation occurs. Thus, mechanically induced neutrophil activation is understood as the competition between two timescales: that of chemical reaction and that of mechanical deformation. The model captures the main features of the experimental observation.

SUBMITTER: Wu T

PROVIDER: S-EPMC4675883 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Publications

Modeling the Mechanosensitivity of Neutrophils Passing through a Narrow Channel.

Wu Tenghu T Feng James J JJ

Biophysical journal 20151201 11

Recent experiments have found that neutrophils may be activated after passing through microfluidic channels and filters. Mechanical deformation causes disassembly of the cytoskeleton and a sudden drop of the elastic modulus of the neutrophil. This fluidization is followed by either activation of the neutrophil with protrusion of pseudopods or a uniform recovery of the cytoskeleton network with no pseudopod. The former occurs if the neutrophil traverses the narrow channel at a slower rate. We pro ...[more]

PMID: 26636935

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Project description:During the multistep process of metastasis, cancer cells encounter various mechanical forces which make them deform drastically. Developing accurate in-silico models, capable of simulating the interactions between the mechanical forces and highly deformable cancer cells, can pave the way for the development of novel diagnostic and predictive methods for metastatic progression. Spring-network models of cancer cell, empowered by our recently proposed identification approach, promises a versatile numerical tool for developing experimentally validated models that can simulate complex interactions at cellular scale. Using this numerical tool, we presented spring-network models of breast cancer cells that can accurately replicate the experimental data of deformation behavior of the cells flowing in a fluidic domain and passing narrow constrictions comparable to microcapillary. First, using high-speed imaging, we experimentally studied the deformability of breast cancer cell lines with varying metastatic potential (MCF-7 (less invasive), SKBR-3 (medium-high invasive), and MDA-MB-231 (highly invasive)) in terms of their entry time to a constricted microfluidic channel. We observed that MDA-MB-231, that has the highest metastatic potential, is the most deformable cell among the three. Then, by focusing on this cell line, experimental measurements were expanded to two more constricted microchannel dimensions. The experimental deformability data in three constricted microchannel sizes for various cell sizes, enabled accurate identification of the unknown parameters of the spring-network model of the breast cancer cell line (MDA-MB-231). Our results show that the identified parameters depend on the cell size, suggesting the need for a systematic procedure for identifying the size-dependent parameters of spring-network models of cells. As the numerical results show, the presented cell models can simulate the entry process of the cell into constricted channels with very good agreements with the measured experimental data.

Dataset Information

Modeling the Mechanosensitivity of Neutrophils Passing through a Narrow Channel.

Publications

Modeling the Mechanosensitivity of Neutrophils Passing through a Narrow Channel.

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