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Register a new userMaintaining the stem cell niche in multicellular models of epithelia
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The maintenance of the proliferative cell niche is critical to epithelial tissue morphology and function. In this paper we investigate how current modelling methods can result in the erroneous loss of proliferative cells from the proliferative cell niche. Using an established model of the inter-follicular epidermis we find there is a limit to the proliferative cell densities that can be maintained in the basal layer (the niche) if we do not include additional mechanisms to stop the loss of proliferative cells from the niche. We suggest a new methodology that enables maintenance of a desired homeostatic population of proliferative cells in the niche: a rotational force is applied to the two daughter cells during the mitotic phase of division to enforce a particular division direction. We demonstrate that this new methodology achieves this goal. This methodology reflects the regulation of the orientation of cell division.
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Since the discovery of a cancer initiating side population in solid tumours, studies focussing on the role of so-called cancer stem cells in cancer initiation and progression have abounded. The biological interrogation of these cells has yielded volumes of information about their behaviour, but there has, as of yet, not been many actionable generalised theoretical conclusions. To address this point, we have created a hybrid, discrete/continuous computational cellular automaton model of a generalised stem-cell driven tissue and explored the phenotypic traits inherent in the inciting cell and the resultant tissue growth. We identify the regions in phenotype parameter space where these initiating cells are able to cause a disruption in homeostasis, leading to tissue overgrowth and tumour formation. As our parameters and model are non-specific, they could apply to any tissue cancer stem-cell and do not assume specific genetic mutations. In this way, our model suggests that targeting these phenotypic traits could represent generalizable strategies across cancer types and represents a first attempt to identify the hallmarks of cancer stem cells.
Bone remodelling maintains the functionality of skeletal tissue by locally coordinating bone-resorbing cells (osteoclasts) and bone-forming cells (osteoblasts) in the form of Bone Multicellular Units (BMUs). Understanding the emergence of such structured units out of the complex network of biochemical interactions between bone cells is essential to extend our fundamental knowledge of normal bone physiology and its disorders. To this end, we propose a spatio-temporal continuum model that integrates some of the most important interaction pathways currently known to exist between cells of the osteoblastic and osteoclastic lineage. This mathematical model allows us to test the significance and completeness of these pathways based on their ability to reproduce the spatio-temporal dynamics of individual BMUs. We show that under suitable conditions, the experimentally-observed structured cell distribution of cortical BMUs is retrieved. The proposed model admits travelling-wave-like solutions for the cell densities with tightly organised profiles, corresponding to the progression of a single remodelling BMU. The shapes of these spatial profiles within the travelling structure can be linked to the intrinsic parameters of the model such as differentiation and apoptosis rates for bone cells. In addition to the cell distribution, the spatial distribution of regulatory factors can also be calculated. This provides new insights on how different regulatory factors exert their action on bone cells leading to cellular spatial and temporal segregation, and functional coordination.
Compiled data for the stem cell numbers, Ns, and division rates, ms, is reanalized in order to show that we can distinguish two groups of human tissues. In the first one, there is a relatively high fraction of maintenance (stem and transit) cells in the tissue, but the division rates are low. The second group, on the other hand, is characterized by very high transit cell division rates, of around one division per day. These groups do not have an embrionary origin. We argue that their properties arise from a combination of the needs of tissue homeostasis (in particular turnover rate) and a bound on cancer risk, which is roughly a linear function of the product Ns ms. The bound on cancer risk leads to a threshold at ms = 8/year, where the fraction of stem cells falls down two orders of magnitude.
Understanding to what extent stem cell potential is a cell-intrinsic property, or an emergent behavior coming from global tissue dynamics and geometry, is a key outstanding question of systems and stem cell biology. Here, we propose a theory of stem cell dynamics as a stochastic competition for access to a spatially-localized niche, giving rise to a stochastic conveyor-belt model. Cell divisions produce a steady cellular stream which advects cells away from the niche, while random rearrangements enable cells away from the niche to be favourably repositioned. Importantly, even when assuming that all cells in a tissue are molecularly equivalent, we predict a common (universal) functional dependence of the long-term clonal survival probability on distance from the niche, as well as the emergence of a well-defined number of functional stem cells, dependent only on the rate of random movements vs. mitosis-driven advection. We test the predictions of this theory on datasets on pubertal mammary gland tips, embryonic kidney tips as well homeostatic intestinal crypt. Importantly, we find good agreement for the predicted functional dependency of the competition as a function of position, and thus functional stem cell number in each organ. This argues for a key role of positional fluctuations in dictating stem cell number and dynamics, and we discuss the applicability of this theory to other settings.
Measurements on embryonic epithelial tissues in a diverse range of organisms have shown that the statistics of cell neighbor numbers are universal in tissues where cell proliferation is the primary cell activity. Highly simplified non-spatial models of proliferation are claimed to accurately reproduce these statistics. Using a systematic critical analysis, we show that non-spatial models are not capable of robustly describing the universal statistics observed in proliferating epithelia, indicating strong spatial correlations between cells. Furthermore we show that spatial simulations using the Subcellular Element Model are able to robustly reproduce the universal histogram. In addition these simulations are able to unify ostensibly divergent experimental data in the literature. We also analyze cell neighbor statistics in early stages of chick embryo development in which cell behaviors other than proliferation are important. We find from experimental observation that cell neighbor statistics in the primitive streak region, where cell motility and ingression are also important, show a much broader distribution. A non-spatial Markov process model provides excellent agreement with this broader histogram indicating that cells in the primitive streak may have significantly weaker spatial correlations. These findings show that cell neighbor statistics provide a potentially useful signature of collective cell behavior.
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