Traumatic brain injuries are serious clinical incidents associated with some of the poorest outcomes in neurological practice. Coupled with the limited regenerative capacity of the brain, this has ...significant implications for patients, carers, and healthcare systems, and the requirement for life-long care in some cases. Clinical treatment currently focuses on limiting the initial neural damage with long-term care/support from multidisciplinary teams. Therapies targeting neuroprotection and neural regeneration are not currently available but are the focus of intensive research. Biomaterial-based interventions are gaining popularity for a range of applications including biomolecule and drug delivery, and to function as cellular scaffolds. Experimental investigations into the development of such novel therapeutics for traumatic brain injury will be critically underpinned by the availability of appropriate high throughput, facile, ethically viable, and pathomimetic biological model systems. This represents a significant challenge for researchers given the pathological complexity of traumatic brain injury. Specifically, there is a concerted post-injury response mounted by multiple neural cell types which includes microglial activation and astroglial scarring with the expression of a range of growth inhibitory molecules and cytokines in the lesion environment. Here, we review common models used for the study of traumatic brain injury (ranging from live animal models to in vitro systems), focusing on penetrating traumatic brain injury models. We discuss their relative advantages and drawbacks for the developmental testing of biomaterial-based therapies.
Root anatomy is an important determinant of root metabolic costs, soil exploration, and soil resource capture. Root anatomy varies substantially within and among plant species. RootSlice is a ...multicellular functional‐structural model of root anatomy developed to facilitate the analysis and understanding of root anatomical phenotypes. RootSlice can capture phenotypically accurate root anatomy in three dimensions of different root classes and developmental zones, of both monocotyledonous and dicotyledonous species. Several case studies are presented illustrating the capabilities of the model. For maize nodal roots, the model illustrated the role of vacuole expansion in cell elongation; and confirmed the individual and synergistic role of increasing root cortical aerenchyma and reducing the number of cortical cell files in reducing root metabolic costs. Integration of RootSlice for different root zones as the temporal properties of the nodal roots in the whole‐plant and soil model OpenSimRoot/maize enabled the multiscale evaluation of root anatomical phenotypes, highlighting the role of aerenchyma formation in enhancing the utility of cortical cell files for improving plant performance over varying soil nitrogen supply. Such integrative in silico approaches present avenues for exploring the fitness landscape of root anatomical phenotypes.
Summary statement
Root anatomy remains an underutilized target for crop breeding. RootSlice, a multicellular functional‐structural model of root anatomy, simulates the costs and benefits of diverse root anatomical phenotypes to estimate their utility for plant fitness in unfavourable soil environments.
In this work, we develop multicellular models of healthy and cancerous human soft tissues, which are used to investigate energy deposition in subcellular targets, quantify the microdosimetric spread ...in a population of cells, and determine how these results depend on model details. Monte Carlo (MC) tissue models combining varying levels of detail on different length scales are developed: microscopically-detailed regions of interest (>1500 explicitly-modelled cells) are embedded in bulk tissue phantoms irradiated by photons (20 keV-1.25 MeV). Specific energy (z; energy imparted per unit mass) is scored in nuclei and cytoplasm compartments using the EGSnrc user-code egs_chamber; specific energy mean, , standard deviation, , and distribution, , are calculated for a variety of macroscopic doses, D. MC-calculated are compared with normal distributions having the same mean and standard deviation. For mGy doses, there is considerable variation in energy deposition (microdosimetric spread) throughout a cell population: e.g. for 30 keV photons irradiating melanoma with 7.5 μm cell radius and 3 μm nuclear radius, for nuclear targets is , and the fraction of nuclei receiving no energy deposition, fz=0, is 0.31 for a dose of 10 mGy. If cobalt-60 photons are considered instead, then decreases to , and fz=0 decreases to 0.036. These results correspond to randomly arranged cells with cell/nucleus sizes randomly sampled from a normal distribution with a standard deviation of 1 μm. If cells are arranged in a hexagonal lattice and cell/nucleus sizes are uniform throughout the population, then decreases to and for 30 keV and cobalt-60, respectively; fz=0 decreases to 0.25 and 0.000 94 for 30 keV and cobalt-60, respectively. Thus, specific energy distributions are sensitive to cell/nucleus sizes and their distributions: variations in specific energy deposited over a cell population are underestimated if targets are assumed to be uniform in size compared with more realistic variation in target size. Bulk tissue dose differs from for nuclei (cytoplasms) by up to () across all cell/nucleus sizes, bulk tissues, and incident photon energies, considering a 50 mGy dose level. Overall, results demonstrate the importance of microdosimetric considerations at low doses, and indicate the sensitivity of energy deposition within subcellular targets to incident photon energy, dose level, elemental compositions, and microscopic tissue model.
We review the basic concepts involved in bioelectrically-coupled multicellular domains, focusing on the role of membrane potentials (Vmem). In the first model, single-cell Vmem is modulated by two ...generic polarizing and depolarizing ion channels, while intercellular coupling is implemented via voltage-gated gap junctions. Biochemical and bioelectrical signals are integrated via a feedback loop between Vmem and the transcription and translation of a protein forming an ion channel. The effective rate constants depend on the single-cell Vmem because these potentials modulate the local concentrations of signaling molecules and ions. This electrochemically-based idealization of the complex biophysical problem suggests that the spatio-temporal map of single-cell potentials can influence downstream patterning processes by means of the voltage-gated gap junction interconnectivity, much as in the case of electronic devices where the control of electric potentials and currents allows the local modulation of the circuitry to achieve full functionality. An alternative theoretical approach, the BioElectrical Tissue Simulation Engine (BETSE), is also presented. The BETSE modeling environment utilizes finite volume techniques to simulate bioelectric states from the perspective of ion concentrations and fluxes. This model has been successfully applied to make predictions and explain experimental observations in a variety of embryonic, regenerative, and oncogenic contexts.
Bioelectric coupling in multicellular domains regulated by voltage-gated gap junctions. Display omitted
•Models for the interplay between biochemical and bioelectric networks are presented.•The bioelectric coupling between cells is modulated by voltage-gated gap junctions.•Multicellular domains may show system-level responses to local changes.•The spatio-temporal map of single-cell potentials modulates multicellular patterning.•This patterning helps regulate embryogenesis, regeneration, and tumorigenesis.
9-Anthracenecarboxylic acid (9-Ac) was reported early as a chloride channel inhibitor and was found to exhibit significant anti-proliferative activity on leukemic cells, but has not been researched ...in solid tumor cells. Herein, a 9-anthraceneic acid derivative was introduced into the cyclometalated Iridium (III) species to construct a novel Iridium (Ir) complex Ir-9-Ac, Ir(ppy)2(9-Ac-L)PF6 (ppy = 2-phenylpyridine, 9-Ac-L = N-((4′-methyl-2,2′-bipyridin-4-yl)methyl)anthracene-9-carboxamide), which could accumulated in lysosomes. Ir-9-Ac showed good cytotoxic activity against several tumor cell lines, notably on A549 cells. Besides Ir-9-Ac could inhibit the cell colony formation and growth of the 3D cell spheroids, demonstrating the potential to suppress tumors in vivo. This design provided a platform for the design of cyclometalated Iridium (III) anticancer complexes.
Ir-9-Ac, Ir(ppy)2(9-Ac-L)PF6 (ppy = 2-phenylpyridine, 9-Ac-L = N-((4′-methyl-2,2′-bipyridin-4-yl)methyl)anthracene-9-carboxamide) exhibited higher activity against solid tumors lines, especially towards A549 cell lines. It was accumulated in the lysosome, and induced cell cycle arrested in phase G0/G1, inhibited the colony formation and activated the endogenous apoptosis genes by an ROS-dependent activation of p38 occurs in response to lysosomal damage. Display omitted
•A metal complex based on nontoxic 9-anthraceneic acid (9-Ac) exerting anti-solid tumor cell effects.•Ir-9-Ac (Ir(ppy)2(9-Ac-L)PF6) is primarily accumulated in the lysosome of A549 cells.•Ir-9-Ac inhibits 3D multicellular tumor spheroids model mimicking the tissue microenvironment.•Ir-9-Ac enhances lysosome damage by a reactive oxygen species-dependent activation of p38 pathway.•Ir-9-Ac induces the endogenous apoptosis in response to lysosomal damage.
•Intercellular Ca2+ waves coordinate the function of multicellular systems.•Determining the origin and velocity of Ca2+ waves in 3D tissue is challenging.•We combined Ca2+ imaging with models to ...study Ca2+ waves in beta cell networks.•The origin and velocity of Ca2+ waves in pancreatic islets are revealed.•Our theoretical and numerical results are of particular value to experimentalists.
Many tissues are gap-junction-coupled syncytia that support cell-to-cell communication via propagating calcium waves. This also holds true for pancreatic islets of Langerhans, where several thousand beta cells work in synchrony to ensure proper insulin secretion. Two emerging functional parameters of islet function are the location of wave initiator regions and the velocity of spreading calcium waves. High-frequency confocal laser-scanning imaging in tissue slices is one of the best available methods to determine these markers, but it is limited to two-dimensional cross-sections of an otherwise three-dimensional islet. Here we show how mathematical modeling can significantly improve this limitation. Firstly, we analytically determine the shape of velocity profiles of spherical excitation waves in the focal plane of a homogeneous three-dimensional space. Secondly, we introduce a mathematical model consisting of coupled excitable cells that considers cellular heterogeneities to approach more realistic conditions by means of numerical simulations. We demonstrate the effectiveness of our approach on experimentally recorded waves from an islet that was stimulated with 9 mM glucose. Furthermore, we show that calcium waves were primarily triggered by a specific region located 30 µm bellow the focal plane at the periphery of the islet. Additionally, we show that the velocity of the calcium wave was around 80 µm/s. We discuss the importance of our approach for the correct determination of the origin and velocity of calcium waves from experimental data, as well as the pitfalls that are due to improper procedural simplifications.
Multicellular transport models for drug have received more attention and research due to a closer physiological structure. A Caco-2/EA.hy926 cell co-culture model was constructed to simulate ...intestinal-vascular barrier. The morphology of microvilli-like and desmosomes structure indicated the tight connection of Caco-2 cells. The apparent permeability coefficient value of phenol red (≤1 × 10−6 cm/s), trans-epithellal electric resistance value (≥300 Ω cm2) and the alkaline phosphatase activity ratio of AP to BL side presented a confluent and integral cell monolayer with well-established differentiation. The microscopic images and vascular endothelial cadherin expression demonstrated the adhesion junction between EA.hy926 cells. The constructed multicellular model differentiated drug transport behavior. The transport potential of EA.hy926 and Caco-2 cells was similar for daidzein and different for daidzin. Combined with multiple evaluation indexes, it could track the multicellular transport process of nanoparticles. The new multicellular model exhibited more in vivo-like characteristics and architecture from intestine to blood, and a potential improvement of in vitro absorption and transport models for drug.
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Diesel exhaust particles (DEP) are a major component of outdoor air pollution. DEP mediated pulmonary effects are plausibly linked to inflammatory and oxidative stress response in which macrophages ...(MQ), epithelial cells and their cell-cell interaction plays a crucial role. Therefore, in this study we aimed at studying the cellular crosstalk between airway epithelial cells with MQ and MQ polarization following exposure to aerosolized DEP by assessing inflammation, oxidative stress, and MQ polarization response markers.
Lung mucosa models including primary bronchial epithelial cells (PBEC) cultured at air-liquid interface (ALI) were co-cultured without (PBEC-ALI) and with MQ (PBEC-ALI/MQ). Cells were exposed to 12.7 μg/cm
aerosolized DEP using XposeALI
. Control (sham) models were exposed to clean air. Cell viability was assessed. CXCL8 and IL-6 were measured in the basal medium by ELISA. The mRNA expression of inflammatory markers (CXCL8, IL6, TNFα), oxidative stress (NFKB, HMOX1, GPx) and MQ polarization markers (IL10, IL4, IL13, MRC1, MRC2 RETNLA, IL12 andIL23) were measured by qRT-PCR. The surface/mRNA expression of TLR2/TLR4 was detected by FACS and qRT-PCR.
In PBEC-ALI exposure to DEP significantly increased the secretion of CXCL8, mRNA expression of inflammatory markers (CXCL8, TNFα) and oxidative stress markers (NFKB, HMOX1, GPx). However, mRNA expressions of these markers (CXCL8, IL6, NFKB, and HMOX1) were reduced in PBEC-ALI/MQ models after DEP exposure. TLR2 and TLR4 mRNA expression increased after DEP exposure in PBEC-ALI. The surface expression of TLR2 and TLR4 on PBEC was significantly reduced in sham-exposed PBEC-ALI/MQ compared to PBEC-ALI. After DEP exposure surface expression of TLR2 was increased on PBEC of PBEC-ALI/MQ, while TLR4 was decreased in both models. DEP exposure resulted in similar expression pattern of TLR2/TLR4 on MQ as in PBEC. In PBEC-ALI/MQ, DEP exposure increased the mRNA expression of anti-inflammatory M2 macrophage markers (IL10, IL4, IL13, MRC1, MRC2).
The cellular interaction of PBEC with MQ in response to DEP plays a pivotal role for MQ phenotypic alteration towards M2-subtypes, thereby promoting an efficient resolution of the inflammation. Furthermore, this study highlighted the fact that cell-cell interaction using multicellular ALI-models combined with an in vivo-like inhalation exposure system is critical in better mimicking the airway physiology compared with traditional cell culture systems.
The existing
models for antitumor drug screening have significant limitations. Many compounds that inhibit two-dimensional (2D) cultured cells do not exhibit the same pharmacological effects
, ...thereby wasting human and material resources and time during drug development. Therefore, it is crucial to develop new models. Three-dimensional (3D) bioprinting technology has greater advantages in constructing human tissues than sandwich culture and organoid construction. We used 3D bioprinting technology to construct a 3D multicellular model of SW480 cells, tumor-associated macrophages, and endothelial cells. The biological activities of the model were evaluated by immunofluorescence, hematoxylin and eosin staining of frozen pathological sections, and transcriptome sequencing. Compared with 3D bioprinted single-cell model (3D printing-S), 3D bioprinted multicellular models (3D printing-M) showed significantly improved expression of tumor-related genes, including hub genes
,
,
,
,
,
,
, and
. Antitumor drug screening experiment showed that the IC
values of 5-FU, oxaliplatin, and irinotecan in 3D printing-S group/2D culture group were 31.13 μM/12.79 μM, 26.79 μM/0.80 μM, and 16.73 μM/10.45 μM, respectively. Compared with the 3D printing-S group, 3D printing-M group was significantly more resistant to chemotherapy.
Purpose: The aim of this study is to build a computational model to investigate the cell dose and cell DNA damage distribution of a multicellular tissue system under the irradiation.
Materials and ...methods: In this work, we developed a computational model for quantifying cell dose and double strand break (DSB) number in a multicellular system by simulating the radiation transport in 2D and 3D cell culture. The model was based on an open-source radiation transport package, Geant4 with Geant4-DNA physics. First, the computational multicellular system was created using a developed program, CelllMaker. Second, the radiation transport simulation for cells was conducted using Geant4 package with the Geant4-DNA physics to obtain the cellular dose and cellular DSB yield.
Results: Using the method described in this work, it is possible to obtain the cellular dose and DNA damage simultaneously. The developed model provides a solution for quantifying the cellular dose and cellular DNA damage which are not easily determined in a radiobiological experiment.
Conclusions: With limited validation data for the model, this preliminary study provides a roadmap for building a comprehensive toolkit for simulating cellular dose and DNA damage of multicellular tissue systems.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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