Morpheus is a modeling environment for the simulation and integration of cell-based models with ordinary differential equations and reaction-diffusion systems. It allows rapid development of ...multiscale models in biological terms and mathematical expressions rather than programming code. Its graphical user interface supports the entire workflow from model construction and simulation to visualization, archiving and batch processing.
Availability and implementation: Binary packages are available at http://imc.zih.tu-dresden.de/wiki/morpheus for Linux, Mac OSX and MS Windows.
Contact:
walter.deback@tu-dresden.de
Supplementary information:
Supplementary data are available at Bioinformatics online.
Living matter equals water, to a first approximation, and water transport across barriers such as membranes and epithelia is vital. Water serves two competing functions. On the one hand, it is the ...fundamental solvent enabling random mobility of solutes and therefore biochemical reactions and intracellular signal propagation. Homeostasis of the intracellular water volume is required such that messenger concentration encodes the stimulus and not inverse volume fluctuations. On the other hand, water flow is needed for transport of solutes to and away from cells in a directed manner, threatening volume homeostasis and signal transduction fidelity of cells. Feedback regulation of fluid transport reconciles these competing objectives. The regulatory mechanisms often span across multiple spatial scales from cellular interactions up to the architecture of organs. Open questions relate to the dependency of water fluxes and steady state volumes on control parameters and stimuli. We here review selected mathematical models of feedback regulation of fluid transport at the cell scale and identify a general “core–shell” structure of such models. We propose that fluid transport models at other spatial scales can be constructed in a generalised core–shell framework, in which the core accounts for the biophysical effects of fluid transport whilst the shell reflects the regulatory mechanisms. We demonstrate the applicability of this framework for tissue lumen growth and suggest future experiments in zebrafish to test lumen size regulation mechanisms.
Morphogenesis, wound healing, and some cancer metastases depend upon the migration of cell collectives that need to be guided to their destination as well as coordinated with other cell movements. ...During zebrafish gastrulation, the extension of the embryonic axis is led by the mesendodermal polster that migrates toward the animal pole, followed by the axial mesoderm that undergoes convergence and extension. Here, we investigate how polster cells are guided toward the animal pole. Using a combination of precise laser ablations, advanced transplants, and functional as well as in silico approaches, we establish that each polster cell is oriented by its immediate follower cells. Each cell perceives the migration of followers, through E-cadherin/α-catenin mechanotransduction, and aligns with them. Therefore, directional information propagates from cell to cell over the whole tissue. Such guidance of migrating cells by followers ensures long-range coordination of movements and developmental robustness.
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•The migration of zebrafish polster cells is oriented by the migration of follower cells•Follower cells orient cells ahead through protrusion formation and pull•Directional information is transmitted through α-catenin mechanotransduction•Guidance by followers allows long-range coordination of different cell populations
Morphogenesis involves the coordination of different cell movements. Boutillon et al. show that the collective migration of zebrafish polster cells relies on “guidance by followers,” where each cell is oriented by the migration of following cells, through α-catenin mechanoperception. The directional information thus propagates across the tissue, ensuring long-range coordination.
Abstract
Motivation
Biological tissues are dynamic and highly organized. Multi-scale models are helpful tools to analyse and understand the processes determining tissue dynamics. These models usually ...depend on parameters that need to be inferred from experimental data to achieve a quantitative understanding, to predict the response to perturbations, and to evaluate competing hypotheses. However, even advanced inference approaches such as approximate Bayesian computation (ABC) are difficult to apply due to the computational complexity of the simulation of multi-scale models. Thus, there is a need for a scalable pipeline for modeling, simulating, and parameterizing multi-scale models of multi-cellular processes.
Results
Here, we present FitMultiCell, a computationally efficient and user-friendly open-source pipeline that can handle the full workflow of modeling, simulating, and parameterizing for multi-scale models of multi-cellular processes. The pipeline is modular and integrates the modeling and simulation tool Morpheus and the statistical inference tool pyABC. The easy integration of high-performance infrastructure allows to scale to computationally expensive problems. The introduction of a novel standard for the formulation of parameter inference problems for multi-scale models additionally ensures reproducibility and reusability. By applying the pipeline to multiple biological problems, we demonstrate its broad applicability, which will benefit in particular image-based systems biology.
Availability and implementation
FitMultiCell is available open-source at https://gitlab.com/fitmulticell/fit.
Polarity is a universal design principle of biological systems that manifests at all organizational scales, yet its coordination across scales remains poorly understood. Here, we make use of the ...extreme anatomical plasticity of planarian flatworms to probe the interplay between global body plan polarity and local cell polarity. Our quantitative analysis of ciliary rootlet orientation in the epidermis reveals a dynamic polarity field with head and tail as independent determinants of anteroposterior (A/P) polarization and the body margin as determinant of mediolateral (M/L) polarization. Mathematical modeling rationalizes the global polarity field and its response to experimental manipulations as superposition of separate A/P and M/L fields, and we identify the core PCP and Ft/Ds pathways as their molecular mediators. Overall, our study establishes a framework for the alignment of cellular polarity vectors relative to planarian body plan landmarks and establishes the core PCP and Ft/Ds pathways as evolutionarily conserved 2D-polarization module.
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•The multi-ciliated planarian epidermis is polarized along the A/P and M/L body axes•Head, tail, and body margin dynamically determines the epidermal polarity field•Core PCP mediates the A/P polarization component•Ft/Ds mediates the M/L polarization component
Ciliary rootlets in the planarian epidermis are globally polarized. Head, tail, and body margin orient the polarity field, which can be modeled by the superposition of independent A/P and M/L polarity components. Vu et al. identify core PCP and Ft/Ds pathways as mediators of the A/P and M/L polarization components.
The cell fate decision of multi-potent pancreatic progenitor cells between the exocrine and endocrine lineages is regulated by Notch signalling, mediated by cell–cell interactions. However, canonical ...models of Notch-mediated lateral inhibition cannot explain the scattered spatial distribution of endocrine cells and the cell-type ratio in the developing pancreas. Based on evidence from acinar-to-islet cell transdifferentiation in vitro, we propose that lateral stabilization, i.e. positive feedback between adjacent progenitor cells, acts in parallel with lateral inhibition to regulate pattern formation in the pancreas. A simple mathematical model of transcriptional regulation and cell–cell interaction reveals the existence of multi-stability of spatial patterns whose simultaneous occurrence causes scattering of endocrine cells in the presence of noise. The scattering pattern allows for control of the endocrine-to-exocrine cell-type ratio by modulation of lateral stabilization strength. These theoretical results suggest a previously unrecognized role for lateral stabilization in lineage specification, spatial patterning and cell-type ratio control in organ development.
Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic ...development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.
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