Computational prediction of strain-dependent diffusion of transcription factors through the cell nucleus

Nava, Michele M.; Fedele, Roberto; Raimondi, Manuela Teresa

doi:10.1007/s10237-015-0737-2

Cited by 17 publications

(20 citation statements)

References 34 publications

(38 reference statements)

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“…In the bone tissue engineering, the scaffolds have to mimic the extracellular matrix physical properties in order to facilitate the cells recruitment, adhesion, proliferation and differentiation [33,34]. As summarized in Table 3, a great variety of scaffold has been developed in accordance with the main requirements of cytocompatibility, osteoinductivity, osteoconductivity.…”

Section: Scaffolds As Cell Supportmentioning

confidence: 99%

Natural and Synthetic Polymers for Bone Scaffolds Optimization

et al. 2020

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Bone tissue is the structural component of the body, which allows locomotion, protects vital internal organs, and provides the maintenance of mineral homeostasis. Several bone-related pathologies generate critical-size bone defects that our organism is not able to heal spontaneously and require a therapeutic action. Conventional therapies span from pharmacological to interventional methodologies, all of them characterized by several drawbacks. To circumvent these effects, tissue engineering and regenerative medicine are innovative and promising approaches that exploit the capability of bone progenitors, especially mesenchymal stem cells, to differentiate into functional bone cells. So far, several materials have been tested in order to guarantee the specific requirements for bone tissue regeneration, ranging from the material biocompatibility to the ideal 3D bone-like architectural structure. In this review, we analyse the state-of-the-art of the most widespread polymeric scaffold materials and their application in in vitro and in vivo models, in order to evaluate their usability in the field of bone tissue engineering. Here, we will present several adopted strategies in scaffold production, from the different combination of materials, to chemical factor inclusion, embedding of cells, and manufacturing technology improvement.

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Section: Scaffolds As Cell Supportmentioning

confidence: 99%

Natural and Synthetic Polymers for Bone Scaffolds Optimization

et al. 2020

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“…Few published examples of numerical simulations address the mechanics of the NPC and its effect on nucleocytoplasmic transport (reviewed in Garcia et al, 2016 ). At the cell scale, our group developed a finite element simulation of passive diffusive fluxes from the cytoplasm to the nucleus, accounting for nuclear deformation (Nava et al, 2015a ). This model coupled nuclear diffusion with local NE deformation in transient conditions, through a strain-dependent diffusion coefficient.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Cell Morphology on the Permeability of the Nuclear Envelope to Diffusive Factors

et al. 2018

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A recent advance in understanding stem cell differentiation is that the cell is able to translate its morphology, i.e., roundish or spread, into a fate decision. We hypothesize that strain states in the nuclear envelope (NE) cause changes in the structure of the nuclear pore complexes. This induces significant changes in the NE's permeability to the traffic of the transcription factors involved in stem cell differentiation which are imported into the nucleus by passive diffusion. To demonstrate this, we set up a numerical model of the transport of diffusive molecules through the nuclear pore complex (NPC), on the basis of the NPC deformation. We then compared the prediction of the model for two different cell configurations with roundish and spread nuclear topologies with those measured on cells cultured in both configurations. To measure the geometrical features of the NPC, using electron tomography we reconstructed three-dimensional portions of the envelope of cells cultured in both configurations. We found non-significant differences in both the shape and size of the transmembrane ring of single pores with envelope deformation. In the numerical model, we thus assumed that the changes in pore complex permeability, caused by the envelope strains, are due to variations in the opening configuration of the nuclear basket, which in turn modifies the porosity of the pore complex mainly on its nuclear side. To validate the model, we cultured cells on a substrate shaped as a spatial micro-grid, called the “nichoid,” which is nanoengineered by two-photon laser polymerization, and induces a roundish nuclear configuration in cells adhering to the nichoid grid, and a spread configuration in cells adhering to the flat substrate surrounding the grid. We then measured the diffusion through the nuclear envelope of an inert green-fluorescent protein, by fluorescence recovery after photobleaching (FRAP). Finally, we compared the diffusion times predicted by the numerical model for roundish vs. spread cells, with the measured times. Our data show that cell stretching modulates the characteristic time needed for the nuclear import of a small inert molecule, GFP, and the model predicts a faster import of diffusive molecules in the spread compared to roundish cells.

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“…3. The characterization of the (an)isotropicity of the biomass intrinsic stress state through the equivalent parameter n demonstrated to be a successful strategy to model the mechanical regulation of culture progression and to link the mechanisms occurring at the micro-scale level to the macroscopic functioning of the growing tissue (see [43]). Model predictions indicate that the parameter n is an effective indicator of the propagation of the isotropic and anisotropic waves within the construct and allows an easy and immediate identification of the adhesion mechanisms developing at the single cell-level, that, accordingly, drive the evolution of the volumetric fraction / v and / n respectively.…”

Section: Discussion Of Simulation Resultsmentioning

confidence: 99%

“…Cartilage tissue growth in engineered constructs had been already studied in a series of papers by Klisch and coauthors [30][31][32]. In this work, we enrich the description of the biophysical phenomena by introducing the conceptual framework developed in [43,45,46]. In these works, the isotropic/anistropic state of the cytoskeletal tension is shown to be responsible for triggering signalling transduction cascades which regulate functional cell behaviors related to proliferation and/or ECM secretion.…”

Section: Introductionmentioning

confidence: 99%

“…According to a finer biomolecular view, this process can be interpreted as due to the fact that the shape of the nucleus is known to regulate the porosity of its membrane and, through this, the import flow of specific transcription Fig. 1 Concept of isotropic/anisotropic stress state of a cell: a a uniform distribution of traction forces (mediated by cell membrane integrin/cadherins) over the cell surface generates an ''isotropic cytoskeletal tension state'' in which the cell nucleus tends to maintain a roundish morphology, favoring ECM secretion; b an ''anisotropic cytoskeletal tension state'' the cell nucleus tends to elongate, favoring cell mitosis factors which regulate cell behavior (we refer to [43] and references therein for a more biologically detailed discussion of these complex processes).…”

Section: Introductionmentioning

confidence: 99%

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A poroelastic mixture model of mechanobiological processes in biomass growth: theory and application to tissue engineering

et al. 2017

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In this article we propose a novel mathematical description of biomass growth that combines poroelastic theory of mixtures and cellular population models. The formulation, potentially applicable to general mechanobiological processes, is here used to study the engineered cultivation in bioreactors of articular chondrocytes, a process of Regenerative Medicine characterized by a complex interaction among spatial scales (from nanometers to centimeters), temporal scales (from seconds to weeks) and biophysical phenomena (fluid-controlled nutrient transport, delivery and consumption; mechanical deformation of a multiphase porous medium). The principal contribution of this research is the inclusion of the concept of cellular ''force isotropy'' as one of the main factors influencing cellular activity. In this description, the induced cytoskeletal tensional states trigger signalling transduction cascades regulating functional cell behavior. This mechanims is modeled by a parameter which estimates the influence of local force isotropy by the norm of the deviatoric part of the total stress tensor. According to the value of the estimator, isotropic mechanical conditions are assumed to be the promoting factor of extracellular matrix production whereas anisotropic conditions are assumed to promote cell proliferation. The resulting mathematical formulation is a coupled system of nonlinear partial differential equations comprising: conservation laws for mass and linear momentum of the growing biomass; advection-diffusion-reaction laws for nutrient (oxygen) transport, delivery and consumption; and kinetic laws for cellular population dynamics. To develop a reliable computational tool for the simulation of the engineered tissue growth process the nonlinear differential problem is numerically solved by: (1) temporal semidiscretization; (2) linearization via a fixed-point map; and (3) finite element spatial approximation. The biophysical accuracy of the mechanobiological model is assessed in the analysis of a simplified 1D geometrical setting. Simulation results show that: (1) isotropic/anisotropic conditions are strongly influenced by both maximum cell specific growth rate and mechanical boundary 123Meccanica (2017) 52: 3273-3297 DOI 10.1007/s11012-017-0638-9 conditions enforced at the interface between the biomass construct and the interstitial fluid; (2) experimentally measured features of cultivated articular chondrocytes, such as the early proliferation phase and the delayed extracellular matrix production, are well described by the computed spatial and temporal evolutions of cellular populations.

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Computational prediction of strain-dependent diffusion of transcription factors through the cell nucleus

Cited by 17 publications

References 34 publications

Natural and Synthetic Polymers for Bone Scaffolds Optimization

Natural and Synthetic Polymers for Bone Scaffolds Optimization

The Effect of Cell Morphology on the Permeability of the Nuclear Envelope to Diffusive Factors

A poroelastic mixture model of mechanobiological processes in biomass growth: theory and application to tissue engineering

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