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Development of a three dimensional multiscale computational model of the human epidermis

Adra, S., Sun, T., MacNeil, S., Holcombe, M. and Smallwood, R. (2010) Development of a three dimensional multiscale computational model of the human epidermis. Plos One , 5 (1). Art. no.e8511 . ISSN 1932-6203

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Transforming Growth Factor (TGF-beta 1) is a member of the TGF-beta superfamily ligand-receptor network. and plays a crucial role in tissue regeneration. The extensive in vitro and in vivo experimental literature describing its actions nevertheless describe an apparent paradox in that during re-epithelialisation it acts as proliferation inhibitor for keratinocytes. The majority of biological models focus on certain aspects of TGF-beta 1 behaviour and no one model provides a comprehensive story of this regulatory factor's action. Accordingly our aim was to develop a computational model to act as a complementary approach to improve our understanding of TGF-beta 1. In our previous study, an agent-based model of keratinocyte colony formation in 2D culture was developed. In this study this model was extensively developed into a three dimensional multiscale model of the human epidermis which is comprised of three interacting and integrated layers: (1) an agent-based model which captures the biological rules governing the cells in the human epidermis at the cellular level and includes the rules for injury induced emergent behaviours, (2) a COmplex PAthway SImulator (COPASI) model which simulates the expression and signalling of TGF-beta 1 at the sub-cellular level and (3) a mechanical layer embodied by a numerical physical solver responsible for resolving the forces exerted between cells at the multi-cellular level. The integrated model was initially validated by using it to grow a piece of virtual epidermis in 3D and comparing the in virtuo simulations of keratinocyte behaviour and of TGF-beta 1 signalling with the extensive research literature describing this key regulatory protein. This research reinforces the idea that computational modelling can be an effective additional tool to aid our understanding of complex systems. In the accompanying paper the model is used to explore hypotheses of the functions of TGF-beta 1 at the cellular and subcellular level on different keratinocyte populations during epidermal wound healing.

Item Type: Article
Copyright, Publisher and Additional Information: © 2010 Adra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Growth-Factor-Beta; Extracellular-Matrix; Transforming Growth-Factor-Beta-1; Transgenic Mice; Wound Closure; Epithelial Homeostasis; Binding-Protein; Gene-Expression; Cell-Migration; In-Vitro
Institution: The University of Sheffield
Academic Units: The University of Sheffield > Faculty of Engineering (Sheffield) > Department of Computer Science (Sheffield)
The University of Sheffield > Faculty of Engineering (Sheffield) > Department of Materials Science and Engineering (Sheffield)
Depositing User: Miss Anthea Tucker
Date Deposited: 16 Feb 2010 09:45
Last Modified: 05 Jun 2014 00:12
Published Version: http://dx.doi.org/10.1371/journal.pone.0008511
Status: Published
Publisher: Public Library Science
Refereed: Yes
Identification Number: 10.1371/journal.pone.0008511
URI: http://eprints.whiterose.ac.uk/id/eprint/10361

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