Collective cell migration is an important process during biological development and tissue repair, but may turn malignant during tumor invasion. Mathematical and computational models are essential to unravel the mechanisms of self-organization that underlie the emergence of collective migration from the interactions among individual cells. Recently, guidance-by-followers was identified as one such underlying mechanism of collective cell migration in the zebrafish embryo. This poses the question how guidance stimuli are integrated when multiple cells interact simultaneously. Here, we extend a recent individual-based model by an integration step of the vectorial guidance stimuli and compare model predictions obtained for various variants of the mechanism (arithmetic mean of stimuli, dominance of stimulus with largest transmission interface, dominance of most head-on stimulus). Simulations are carried out and quantified within the modeling and simulation framework Morpheus. Collective cell migration is sfound to be robust and qualitatively identical for all considered variants of stimulus integration. Moreover, this study highlights the role of individual-based modeling approaches for understanding collective phenomena at the population scale that emerge from cell-cell interactions.

/pdf/collective-cell-migration-due-to-guidance-by-followers-is-uo341fr0.pdf

Collective cell migration due to guidance-by-followers is robust to multiple stimuli

Collective cell migration is an important process during biological development and tissue repair but may turn malignant during tumor invasion. Mathematical and computational models are essential to unravel the mechanisms of self-organization that underlie the emergence of collective migration from the interactions among individual cells. Recently, guidance-by-followers was identified as one such underlying mechanism of collective cell migration in the embryo of the zebrafish. This poses the question of how the guidance stimuli are integrated when multiple cells interact simultaneously. In this study, we extend a recent individual-based model by an integration step of the vectorial guidance stimuli and compare model predictions obtained for different variants of the mechanism (arithmetic mean of stimuli, dominance of stimulus with largest transmission interface, and dominance of most head-on stimulus). Simulations are carried out and quantified within the modeling and simulation framework Morpheus. Collective cell migration is found to be robust and qualitatively identical for all considered variants of stimulus integration. Moreover, this study highlights the role of individual-based modeling approaches for understanding collective phenomena at the population scale that emerge from cell-cell interactions. 

pdf/collective-cell-migration-due-to-guidance-by-followers-is-fh16nurdby.pdf

Abstract While pancreatic beta-cell proliferation has been extensively studied, the role of cell death during islet development remains incompletely understood. Using a genetic model of caspase inhibition in beta cells coupled with mathematical modeling, we here discover an onset of beta-cell death in juvenile zebrafish, which regulates beta-cell mass. Histologically, this beta-cell death is underestimated due to phagocytosis by resident macrophages. To investigate beta-cell apoptosis at the molecular level, we implement a conditional model of beta-cell death linked to Ca 2+ overload. Transcriptomic analysis reveals that metabolically-stressed beta cells follow paths to either de-differentiation or apoptosis. Beta cells destined to die activate inflammatory and immuno-regulatory pathways, suggesting that cell death regulates the crosstalk with immune cells. Consistently, inhibiting beta-cell death during development reduces pro-inflammatory resident macrophages and expands T-regulatory cells, the deficiency of which causes premature activation of NF-kB signaling in beta cells. Thus, developmental cell death not only shapes beta-cell mass but it also influences the islet’s inflammatory milieu by shifting the immune-cell population towards pro-inflammatory. 

Developmental beta-cell death orchestrates the islet’s inflammatory milieu by regulating immune system crosstalk

Morphogenesis, wound healing, and some cancer metastases rely on the collective migration of groups of cells. In these processes, guidance and coordination between cells and tissues are critical. While strongly adherent epithelial cells have to move collectively, loosely organized mesenchymal cells can migrate as individual cells. Nevertheless, many of them migrate collectively. This article summarizes how migratory reactions to cell-cell contacts, also called "contact regulation of locomotion" behaviors, organize mesenchymal collective cell migration. It focuses on one recently discovered mechanism called "guidance by followers", through which a cell is oriented by its immediate followers. In the gastrulating zebrafish embryo, during embryonic axis elongation, this phenomenon is responsible for the collective migration of the leading tissue, the polster, and its guidance by the following posterior axial mesoderm. Such guidance of migrating cells by followers ensures long-range coordination of movements and developmental robustness. Along with other "contact regulation of locomotion" behaviors, this mechanism contributes to organizing collective migration of loose populations of cells.

Organizing collective cell migration through guidance by followers.

Collective alignment of cell populations is a commonly observed phenomena in biology. An important example are aligning fibroblasts in healthy or scar tissue. In this work we derive and simulate a mechanistic agent-based model of the collective behaviour of actively moving and interacting cells, with a focus on understanding collective alignment. The derivation strategy is based on energy minimisation. The model ingredients are motivated by data on the behaviour of different populations of aligning fibroblasts and include: Self-propulsion, overlap avoidance, deformability, cell-cell junctions and cytoskeletal forces. We find that there is an optimal ratio of self-propulsion speed and overlap avoidance that maximises collective alignment. Further we find that deformability aids alignment, and that cell-cell junctions by themselves hinder alignment. However, if cytoskeletal forces are transmitted via cell-cell junctions we observe strong collective alignment over large spatial scales.

Derivation and simulation of a computational model of active cell populations: How overlap avoidance, deformability, cell-cell junctions and cytoskeletal forces affect alignment

Motivation Biological tissues are dynamic and highly organized. Multi-scale models are helpful tools to analyze 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 FitMultiCell is available open-source at https://gitlab.com/fitmulticell/fit. Contact jan.hasenauer@uni-bonn.de Supplementary information Supplementary data are available at https://doi.org/10.5281/zenodo.7646287 online.

/pdf/fitmulticell-simulating-and-parameterizing-computational-2frtnado.pdf

FitMultiCell: Simulating and parameterizing computational models of multi-scale and multi-cellular processes

Background Stillbirths during pregnancy do not only trigger maternal psychological trauma but also affect the economic growth in developing countries. Since the predictors of stillbirths and their dynamics are diverse in different settings, it requires adequate knowledge to mitigate these predictors in reducing perinatal deaths in Ghana. This study aimed to determine the prevalence and determinants of stillbirths in a referral hospital in Northern Region of Ghana. Methods This study is a portion of a retrospective cohort study conducted from April to July 2020 in Savelugu municipality of Northern Ghana. Sociodemographic and obstetric data were collected using a structured questionnaire from antenatal and delivery records. We used binary logistic regression to identify independent predictors of stillbirths. Results Four percent (4.0%) of the 422 deliveries were stillborns. Anaemia in the first trimester of pregnancy (aOR: 3.15; 95%CI: 0.94 - 10.6; p=0.034), self-employed mothers (aOR: 7.75; 95%CI: 2.33 - 25.8; p=0.018), and non-use of insecticide-treated bed nets during pregnancy (aOR: 12.9; 95%CI: 1.55 - 107; p=0.001) were independent predictors of stillbirths. Conclusion The relatively high stillbirth prevalence at the referral facility is affected by gestational anaemia and lifestyle factors including non-use of insecticide-treated bed nets and self-employed jobs. Management of Savelugu Municipal Hospital (Ghana Health Service), program planners, and other stakeholders who are engaged in improving perinatal and maternal health should be made aware of these predictors in order to reduce the stillbirth rate and its psychological effect on families in Savelugu.

Predictors of stillbirths in a peri-urban referral facility in Northern Region, Ghana

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Collective cell migration due to guidance-by-followers is robust to multiple stimuli

FitMultiCell: Simulating and parameterizing computational models of multi-scale and multi-cellular processes

Predictors of stillbirths in a peri-urban referral facility in Northern Region, Ghana