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1.
J Theor Biol ; 575: 111613, 2023 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-37774939

RESUMO

Cells rely on their cytoskeleton for key processes including division and directed motility. Actin filaments are a primary constituent of the cytoskeleton. Although actin filaments can create a variety of network architectures linked to distinct cell functions, the microscale molecular interactions that give rise to these macroscale structures are not well understood. In this work, we investigate the microscale mechanisms that produce different branched actin network structures using an iterative classification approach. First, we employ a simple yet comprehensive agent-based model that produces synthetic actin networks with precise control over the microscale dynamics. Then we apply machine learning techniques to classify actin networks based on measurable network density and geometry, identifying key mechanistic processes that lead to particular branched actin network architectures. Extensive computational experiments reveal that the most accurate method uses a combination of supervised learning based on network density and unsupervised learning based on network symmetry. This framework can potentially serve as a powerful tool to discover the molecular interactions that produce the wide variety of actin network configurations associated with normal development as well as pathological conditions such as cancer.


Assuntos
Actinas , Simulação de Dinâmica Molecular , Actinas/metabolismo , Citoesqueleto de Actina/metabolismo
2.
Mol Biol Cell ; 34(5): ar48, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36989037

RESUMO

Recent research has elucidated mechanochemical pathways of single cell polarization, but much less is known about collective motility initiation in adhesive cell groups. We used galvanotactic assays of zebrafish keratocyte cell groups, pharmacological perturbations, electric field switches, particle imaging velocimetry, and cell tracking to show that large cell groups initiate motility in minutes toward the cathode. Interestingly, while PI3K-inhibited single cells are biased toward the anode, inhibiting PI3K does not affect the cathode-directed cell group migration. We observed that control groups had the fastest cathode-migrating cell at the front, while the front cells in PI3K-inhibited groups were the slowest. Both control and PI3K-inhibited groups rapidly repolarized when the electric field direction was reversed, and the group migration continued after the electric field was switched off. Inhibiting myosin disrupted the cohesiveness of keratocyte groups and abolished the collective directionality and ability to switch direction when the electric field is reversed. Our data are consistent with a model according to which cells in the group sense the electric field individually and mechanical integration of the cells results in coherent group motility.


Assuntos
Fosfatidilinositol 3-Quinases , Peixe-Zebra , Animais , Movimento Celular
3.
Elife ; 102021 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-34842140

RESUMO

Physiological and pathological morphogenetic events involve a wide array of collective movements, suggesting that multicellular arrangements confer biochemical and biomechanical properties contributing to tissue-scale organization. The Ciona cardiopharyngeal progenitors provide the simplest model of collective cell migration, with cohesive bilateral cell pairs polarized along the leader-trailer migration path while moving between the ventral epidermis and trunk endoderm. We use the Cellular Potts Model to computationally probe the distributions of forces consistent with shapes and collective polarity of migrating cell pairs. Combining computational modeling, confocal microscopy, and molecular perturbations, we identify cardiopharyngeal progenitors as the simplest cell collective maintaining supracellular polarity with differential distributions of protrusive forces, cell-matrix adhesion, and myosin-based retraction forces along the leader-trailer axis. 4D simulations and experimental observations suggest that cell-cell communication helps establish a hierarchy to align collective polarity with the direction of migration, as observed with three or more cells in silico and in vivo. Our approach reveals emerging properties of the migrating collective: cell pairs are more persistent, migrating longer distances, and presumably with higher accuracy. Simulations suggest that cell pairs can overcome mechanical resistance of the trunk endoderm more effectively when they are polarized collectively. We propose that polarized supracellular organization of cardiopharyngeal progenitors confers emergent physical properties that determine mechanical interactions with their environment during morphogenesis.


Assuntos
Comunicação Celular , Movimento Celular , Polaridade Celular , Ciona intestinalis/embriologia , Células-Tronco/fisiologia , Animais , Embrião não Mamífero/embriologia
4.
Nat Mater ; 20(3): 410-420, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33077951

RESUMO

Contractile actomyosin networks are responsible for the production of intracellular forces. There is increasing evidence that bundles of actin filaments form interconnected and interconvertible structures with the rest of the network. In this study, we explored the mechanical impact of these interconnections on the production and distribution of traction forces throughout the cell. By using a combination of hydrogel micropatterning, traction force microscopy and laser photoablation, we measured the relaxation of traction forces in response to local photoablations. Our experimental results and modelling of the mechanical response of the network revealed that bundles were fully embedded along their entire length in a continuous and contractile network of cortical filaments. Moreover, the propagation of the contraction of these bundles throughout the entire cell was dependent on this embedding. In addition, these bundles appeared to originate from the alignment and coalescence of thin and unattached cortical actin filaments from the surrounding mesh.


Assuntos
Epitélio Pigmentado da Retina/citologia , Fibras de Estresse/fisiologia , Citoesqueleto de Actina/fisiologia , Actinas/metabolismo , Actinas/ultraestrutura , Fenômenos Biomecânicos , Linhagem Celular , Microscopia Crioeletrônica , Módulo de Elasticidade , Humanos , Hidrogéis/química , Microscopia de Força Atômica , Modelos Biológicos , Epitélio Pigmentado da Retina/fisiologia
7.
Mol Biol Cell ; 31(15): 1637-1649, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32459563

RESUMO

Polarization is a crucial component in cell differentiation, development, and motility, but its details are not yet well understood. At the onset of cell locomotion, cells break symmetry to form well-defined cell fronts and rears. This polarity establishment varies across cell types: in Dictyostelium discoideum cells, it is mediated by biochemical signaling pathways and can function in the absence of a cytoskeleton, while in keratocytes, it is tightly connected to cytoskeletal dynamics and mechanics. Theoretical models that have been developed to understand the onset of polarization have explored either signaling or mechanical pathways, yet few have explored mechanochemical mechanisms. However, many motile cells rely on both signaling modules and actin cytoskeleton to break symmetry and achieve a stable polarized state. We propose a general mechanochemical polarization model based on coupling between a stochastic model for the segregation of signaling molecules and a simplified mechanical model for actin cytoskeleton network competition. We find that local linear coupling between minimally nonlinear signaling and cytoskeletal systems, separately not supporting stable polarization, yields a robustly polarized cell state. The model captures the essence of spontaneous polarization of neutrophils, which has been proposed to emerge due to the competition between frontness and backness pathways.


Assuntos
Polaridade Celular , Modelos Biológicos , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Fenômenos Biomecânicos , Transdução de Sinais , Processos Estocásticos
8.
Biophys J ; 112(12): 2672-2682, 2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28636923

RESUMO

Cells employing amoeboid motility exhibit repetitive cycles of rapid expansion and contraction and apply coordinated traction forces to their environment. Although aspects of this process are well studied, it is unclear how the cell controls the coordination of cell length changes with adhesion to the surface. Here, we develop a simple model to mechanistically explain the emergence of periodic changes in length and spatiotemporal dynamics of traction forces measured in chemotaxing unicellular amoeba, Dictyostelium discoideum. In contrast to the biochemical mechanisms that have been implicated in the coordination of some cellular processes, we show that many features of amoeboid locomotion emerge from a simple mechanochemical model. The mechanism for interaction with the environment in Dictyostelium is unknown and thus, we explore different cell-environment interaction models to reveal that mechanosensitive adhesions are necessary to reproduce the spatiotemporal adhesion patterns. In this modeling framework, we find that the other motility modes, such as smooth gliding, arise naturally with variations in the physical properties of the surface. Thus, our work highlights the prominent role of biomechanics in determining the emergent features of amoeboid locomotion.


Assuntos
Adesão Celular/fisiologia , Dictyostelium/fisiologia , Mecanotransdução Celular/fisiologia , Actinas/metabolismo , Actomiosina/metabolismo , Membrana Celular/fisiologia , Citoesqueleto/fisiologia , Citosol/metabolismo , Meio Ambiente , Modelos Biológicos , Movimento/fisiologia , Polimerização , Propriedades de Superfície
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