Understanding the regulation of epidermal tissue thickness by cellular and subcellular processes using multiscale modelling
AuthorMiller, Claire Margaret
AffiliationSchool of Mathematics and Statistics
Document TypePhD thesis
Access StatusOpen Access
© 2020 Claire Margaret Miller
The epidermis is the outermost layer of the skin, providing a protective barrier for our bodies. Two important aspects to the barrier function of the epidermis are maintenance of its barrier layer and constant cell turnover. The main barrier layer in the epidermis is the outermost layer, called the stratum corneum. This layer blocks both the entry of antigens and the loss of internal water and solutes. If antigens do enter the system, cell turnover has been hypothesised to propel them out the system by providing a constant upwards velocity of cells which carry the toxins with them. The majority of severe diseases of the epidermis relate to a reduction in thickness of the stratum corneum. Decreased thickness reduces the barrier function of the layer, causing discomfort and inflammation. Due to its importance to barrier function, the maintenance of stratum corneum thickness, and consequently overall tissue thickness, is the focus of this thesis. In order to maintain both stratum corneum thickness and overall tissue thickness it is necessary for the system to balance cell proliferation and cell loss. Cell loss in the epidermis occurs when dead cells at the top of the tissue are lost to the environment through a process called desquamation. Cell proliferation occurs in the base, or basal, layer. As the basal cells proliferate, cells above them are pushed upwards through the tissue, causing constant upwards movement in the tissue. Not only does this contribute directly to the barrier function through the cell turnover as discussed above, but the velocity of the cells is likely to be key in regulating the tissue thickness. Assuming the cell loss occurs at a fairly constant rate, the combination of the velocity and the loss rate determine tissue thickness. In order to investigate these processes we develop a three dimensional discrete, multiscale, multicellular model, focussing on maintenance of cell proliferation and desquamation. Using this model, we are able to investigate how subcellular and cellular level processes interact to maintain a homeostatic tissue. Our model is able to reproduce a system that self-regulates its thickness. The first aspect of this regulation is maintaining a constant rate of proliferation in the epidermis, and consequently a constant upwards velocity of cells. The second aspect is a maintained rate of desquamation. The model shows that hypothesised biological models for the degradation of cell-cell adhesion from the literature are able to provide a consistent rate of cell loss which balances proliferation. An investigation into a disorder which disrupts this desquamation model shows reduced tissue thickness, consequently diminishing the protective role of the tissue. In developing the multiscale model we have begun to delve deeper into the relationship between subcellular and cellular processes and epidermal tissue structure. The model is developed with scope for the integration of further subcellular processes. This provides it with the potential for further experiments into the causes and effects of behaviours and diseases of the epidermis, with much higher time and cost efficiency than other experimental methods.
Keywordsmultiscale modelling; epidermis; multicellular modelling; computational biology; overlapping spheres; agent based modelling; mathematical biology; desquamation
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