PhysiMeSS - a new physiCell addon for extracellular matrix modelling

Abstract

The extracellular matrix, composed of macromolecules like collagen fibres, provides structural support to cells and acts as a barrier that metastatic cells degrade to spread beyond the primary tumour. While agent-based frameworks, such as PhysiCell, can simulate the spatial dynamics of tumour evolution, they only implement cells as circles (2D) or spheres (3D). To model the extracellular matrix as a network of fibres, we require a new type of agent represented by line segments (2D) or cylinders (3D). Here, we present PhysiMeSS, an addon of PhysiCell, introducing a new agent type to describe fibres and their physical interactions with cells and other fibres. PhysiMeSS implementation is available at https://github.com/PhysiMeSS/PhysiMeSS and in the official PhysiCell repository. We provide examples describing the possibilities of this framework. This tool may help tackle important biological questions, such as diseases linked to dysregulation of the extracellular matrix or the processes leading to cancer metastasis.

Editors Assessment:

PhysiCell is an open source multicellular systems simulator for studying many interacting cells in dynamic tissue microenvironments. As part of the PhysiCell ecosystem of tools and modules this paper presents a PhysiCell addon, PhysiMeSS (MicroEnvironment Structures Simulation) which allows the user to accurately represent the extracellular matrix (ECM) as a network of fibres. This can specify rod-shaped microenvironment elements such as the matrix fibres (e.g. collagen) of the ECM, allowing the PhysiCell user the ability to investigate physical interactions with cells and other fibres. Reviewers asked for additional clarification on a number of features. And the paper now clear future releases will provide full 3D compatibility and include working on fibrogenesis, i.e. the creation of new ECM fibres by cells.

This evaluation refers to version 1 of the preprint

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AbstractThe extracellular matrix is a complex assembly of macro-molecules, such as collagen fibres, which provides structural support for surrounding cells. In the context of cancer metastasis, it represents a barrier for the cells, that the migrating cells needs to degrade in order to leave the primary tumor and invade further tissues. Agent-based frameworks, such as PhysiCell, are often use to represent the spatial dynamics of tumor evolution. However, typically they only implement cells as agents, which are represented by either a circle (2D) or a sphere (3D). In order to accurately represent the extracellular matrix as a network of fibres, we require a new type of agent represented by a segment (2D) or a cylinder (3D).In this article, we present PhysiMeSS, an addon of PhysiCell, which introduces a new type of agent to describe fibres, and their physical interactions with cells and other fibres. PhysiMeSS implementation is publicly available at https://github.com/PhysiMeSS/PhysiMeSS, as well as in the official Physi-Cell repository. We also provide simple examples to describe the extended possibilities of this new framework. We hope that this tool will serve to tackle important biological questions such as diseases linked to dis-regulation of the extracellular matrix, or the processes leading to cancer metastasis.

This work has been published in GigaByte Journal under a CC-BY 4.0 license (https://doi.org/10.46471/gigabyte.136), and has published the reviews under the same license. It is also part of GigaByte’s PhysiCell Ecosystem series for tools that utilise or build upon the PhysiCell platform: https://doi.org/10.46471/GIGABYTE_SERIES_0003 These reviews are as follows.

Reviewer 1. Erika Tsingos

One important aspect that the authors need to be aware of and mention explicitly is that their algorithm for fiber set-up leads to differences in fiber concentration and orientation at the boundary, because fibers that are not wholly contained in the simulation box are discarded. The effect of this choice can be seen upon close inspection of Figure 2: In the left panel, fibers align tangentially to the boundary, so locally the orientation is not isotropic. Similarly, in Figure 2 middle and right panels, the left and right boundaries have lower local fiber concentration. This issue could potentially affect the outcome of a simulation, so it's important that readers are made aware so that if necessary they can address this with a modified algorithm. ----- Minor comments: In the abstract, the phrasing implies agent-based frameworks are only used for tumour evolution. I would rephrase such that it is clear that tumour evolution is one example among many possible applications. I suggest adding a dash to improve readability in the following sentence in the introduction: "However, we note that the applications of PhysiMeSS stretch beyond those wanting to model the ECM -- as the new cylindrical/rod-shaped agents could be used to model blood vessel segments or indeed create obstacles within the domain." In the implementation section, add a short sentence to clarify if PhysiMeSS is "backwards compatible" with older PhysiCell models that do not use the fiber agent. Notation in equations: A single vertical line is absolute value, and two vertical lines is Euclidean norm? The explanation of Equation 1 implies that the threshold v_{max} should limit the parallel force, but the text does not explicitly say if ||v|| is restricted to be less or equal to v_{max}. Is that the case? In Equation 2, I don't see the need to square the terms in parenthesis. If |v*l_f| is an absolute value it is always positive. Since l_f is normalized the value of the dot product is only between 0 and the magnitude of v. Am I missing something? Are p_x and p_y in the moment arm magnitude coordinates with respect to the fiber center? Table 2: It would be helpful to have a separate column with the corresponding symbols used throughout the text and equations. Figure 5/6: Missing crosslinker color legend. ----- Typos/grammar: "As an aside, an not surprisingly," --> As an aside, and not surprisingly, "This may either be because as a cell tries to migrate through the domain fibres which act as obstacles in the cell’s path," --> remove the word "which"

Reviewer 2. Jinseok Park

Noel et al. introduce PhysiMess - a new PhysiCell Addon for ECM remodeling. This new addon is a powerful tool to simulate ECM remodeling and has the potential to be applied to mechanobiology research, which makes my enthusiasm high. I would like to give a few suggestions.

Basically, it is an addon of PhysiCell. So, I suggest describing PhysiCell and how to add the addon for readers who are not familiar with these tools. Also, screen captures of tool manipulation would be very helpful.
Figure 2 and 3 exhibit the outcome of the addon showing ECM remodeling. I would suggest to show actual ECM images modeled by the addon.
The equations reflect four interactions, and in my understanding, the authors describe cell-fibre, fiber-cell, and fiber-fiber interactions. I suggest generating an example corresponding to each interaction's modulation and explaining how the add-on results explain the physiological phenomena. For instance, focal adhesion may be a key modulator of cell-fibre or fiber-cell interaction, presumably, alpha or beta fiber. I would demonstrate how the different parameters generate different results and explain the physiological situation modeled by the results.
Similarly, Figure 5 and Figure 6 only show one example and no comparison with other conditions. For example, It would be better to exhibit no pressure/pressure conditions. It may help readers estimate how the pressure impacts cell proliferation.

Reviewer 3. Simon Syga

The presented paper "PhysiMeSS - A New PhysiCell Addon for Extracellular Matrix Modelling" is a useful extension to the popular simulation framework PhysiCell. It enables the simulation of cell populations interacting with the extracellular matrix, which is represented by a set of line segments (2D) or cylinders (3D). These represend a new kind of agent in the simulation framework. The paper outlines the basic implementation, properties and interactions of these agents. I recommend publication after a small set of minor issues have been addressed. Please refer to the attached marked-up PDF file for these minor issues and suggestions. https://gigabyte-review.rivervalleytechnologies.comdownload-api-file?ZmlsZV9wYXRoPXVwbG9hZHMvZ3gvVFIvNTUwL2d4LVRSLTE3MTk5NDYwNjlfU1kucGRm

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PhysiMeSS - a new physiCell addon for extracellular matrix modelling

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