西亚试剂：Skin Stem Cell Hypotheses and Long Term Clone Survival – Ex

发布时间：2025-05-18

Skin Stem Cell Hypotheses and Long Term Clone Survival – Explored Using Agent-based Modelling

X. Li, A. K. Upadhyay, A. J. Bullock, T. Dicolandrea, J. Xu, R. L. Binder, M. K. Robinson, D. R. Finlay, K. J. Mills, C. C. Bascom, C. K. Kelling, R. J. Isfort, J. W. Haycock, S. MacNeil & R. H. Smallwood

Skin is the body's first line of defense against environmental hazards, forming a protective barrier for the surface of the body. It consists of an epidermis and a dermis separated by a basement membrane. Keratinocytes are the main building blocks of the epidermis. Under normal conditions, cells on the skin surface are continuously replaced by new cells generated in the basal layer. Cells leave the basal layer and differentiate upwards to comprise the stratum spinosum, stratum granulosum and stratum corneum. These upper layers mediate skin barrier function. The lifespan of keratinocytes and their differentiation into a barrier to prevent water loss and infection are precisely regulated in order to achieve coordinated self-renewal by a process called homeostasis.

Due to the dynamic nature of skin and the importance of its structural integrity, it is difficult to study the development of the tissue in vivo, as any disturbance in the epidermis (such as tape stripping or sodium dodecyl sulphate treatment) compromises the barrier function immediately and many of the experimental techniques used to study cell biology cannot ethically be carried out in man. Therefore, animal models and in vitro tissue engineered skin are commonly used as alternatives. Although these experiments provide a good representation of the human in vivo equivalent, the results are usually qualitative and difficult to interpret on a continuum basis, which hinders integrating new discoveries with previous research. Computer models on the other hand, are ideal tools for investigating individual cell behaviour by combining laboratory data and the existing literature. Agent-based models have been frequently used for studying a group of entities (or agents)1, 2, 3, such as keratinocytes, each with their unique properties4, 5. The behaviour of each agent is defined using a set of rules based on the experimental literature. Previous models of epithelial cells have been used in studying a wide range of applications, such as cell culture morphogenesis6, hierarchy of cells within the intestinal crypts7, 8, activation of hematopoietic stem cells9, the behaviour of sperm in the oviduct10, and modelling metabolic process in liver cells11. In particular, epithelial cells in the intestinal crypts are famous for their monoclonality, where a single stem cell lineage is thought to sustain the entire population in each crypt7, 8. This has been shown by Loeffler et al. (1997) through their 2D models by applying a stochastic symmetric division pattern to stem cells7. The model was later extended by Van Leeuwen et al. (1997) to investigate the process of mitosis and clonal expansion in the crypt8. In addition, agent-based models have also been used extensively to simulate tissue regeneration under pathological conditions, such as the remodelling of airway epithelium in asthma12, the acute inflammatory response13, elucidating possible mechanisms for psoriasis14, cancer cell invasion and tumour behaviour15, as well as a range of multi-scaled models aimed at bridging between changes at the cellular level with behaviours at the tissue and the organ levels1, 8, 12, 16, 17. These models allow one to explore alternative hypotheses inexpensively and for longer periods than are possible for in vitro experiments making them very useful for studying the dynamics of biological organisation.

In skin biology, epithelial homeostasis and self-renewal supported by regenerative cells is one of the most studied areas. As new data emerge hypotheses behind the behaviour of regenerative cells have also evolved over the past years. In particular, a series of recent publications18, 19 challenged the traditional view of a stem-transit amplifying (TA) cell population leading to the generation of an epithelial proliferation unit (EPU), which in turn sustains the renewal process in the tissue. By employing genetic labelling techniques, these studies followed colonies of regenerative cells over one year, and suggested an alternative hypothesis of division in the basal layer (see Figure 1). This hypothesis, described in Clayton et al. (2007)18, is in favour of a single proliferative progenitor cell population that sustains epithelial renewal by producing post mitotic basal cells in a stochastic process. The experiments however, provided insufficient evidence for slow-cycling stem cells as had previously been suggested. However, recent evidence20 suggests the existence of a hierarchical organisation consisting of both fast-cycling progenitor cells and slow-cycling stem cells in an attempt to consolidate the traditional stem-TA hypothesis with stochastic fate decision (hereon referred to as the “PAS” hypothesis, short for populational asymmetry with stem cells). All three hypotheses have been derived based on the observation of the dynamics of biological tissues over a steady state period of typically one year. Individually, each provides a sound mechanism that ensures the continuous regeneration during homeostasis. However, these hypotheses are derived from a collection of static snap-shots of tissues at regular intervals and hence provide a limited window of information within the lifespan of the tissue. A similar problem lies with the in vitro experiments, from which data can only be obtained over a few weeks. In contrast, these hypotheses can be used to generate rule sets which can run inexpensively using computer models, which can: (1) monitor the entire population over any numerical period; and (2) trace the development of individual lineages over years within the equivalent of days in computational time.

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