Correlating Cell Behavior with Tissue Topology in Embryonic Epithelia

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.Comment: PLoS one 201

The mechanics of mitotic cell rounding

When animal cells enter mitosis, they round up to become spherical. This shape change is accompanied by changes in mechanical properties. Multiple studies using different measurement methods have revealed that cell surface tension, intracellular pressure and cortical stiffness increase upon entry into mitosis. These cell-scale, biophysical changes are driven by alterations in the composition and architecture of the contractile acto-myosin cortex together with osmotic swelling and enable a mitotic cell to exert force against the environment. When the ability of cells to round is limited, for example by physical confinement, cells suffer severe defects in spindle assembly and cell division. The requirement to push against the environment to create space for spindle formation is especially important for cells dividing in tissues. Here we summarize the evidence and the tools used to show that cells exert rounding forces in mitosis in vitro and in vivo, review the molecular basis for this force generation and discuss its function for ensuring successful cell division in single cells and for cells dividing in normal or diseased tissues

Responses of epithelial monolayers to an imposed deformation

Epithelial monolayers are a class of animal tissue which comprise some of the most basic and important structures in metazoans. Many remarkable morphogenetic events, responsible for determining adult tissue shape, take place in epithelia and they continue to perform crucial functions throughout adult life. Whether it is the filling of the bladder or during a precise morphogenetic transformation, epithelia must frequently undergo or drive tissue deformations. Therefore, much effort has been directed towards understanding the combination of material properties and cellular behaviours which determine how epithelia respond to the application of stress and strain. The complex biophysical environment of in vivo tissues, however, can hinder attempts to understand the underlying mechanisms and principles at play. To address this, a novel and highly simplified system is utilised in which uniaxial strain is applied to epithelia monolayers which are devoid of a substrate. Application of compressive strain to these suspended epithelia unexpectedly revealed their ability to autonomously flatten buckles and remodel cell shape as the tissue mechanically adapts to a new shorter length over a duration of ~60 seconds. These changes, which are found to be driven by actomyosin contractility, appear fully reversible since the epithelia can readapt to their initial length when it is restored and maintained over a similar time period. At longer timescales, cell division within the epithelia is also found to be affected by the application of strain. Both compressive and tensile strain causes an alignment of division orientation which is demonstrated to be due to a global realignment of cell long axes combined with orientation of division along these axes, rather than by cells detecting and responding to long-range tissue stress orientation. In turn, these strain-oriented cell divisions homeostatically alter tissue organisation by redistributing cell mass along the direction of division and ultimately restore isotropic cell shape

The Effects of Oncogenic Ras on Epithelial Cell Division

The devastating diagnosis of cancer arises in part from the deregulation of cell division. However, it is not known how these cells divide across the range of environments encountered during cancer progression. In this thesis, I investigate the effects of oncogenic Ras on the biology of epithelial cell division. Through this work I find that Ras-ERK signalling not only increases mitotic rounding but also alters the dynamics and division axis of cells as they divide and respread. This reduces the ability of nascent daughters to assume the mother cell footprint and appears to result from effects on cell adhesion that normally provide a memory of cell shape. Significantly, these effects occur within five hours of oncogene expression and are rapidly inhibited by Ras-ERK inhibitors. Together, these findings show how activation of a single oncogene can directly change the fundamental act of cell division as a relatively early event in oncogenesis

A single cell based model for cell divisions with spontaneous topology changes

The development of multicellular organisms is accompanied by the formation of tis- sues of precise shapes, sizes and topologies. Remarkable similarities between tissue topologies, in particular proliferating epithelial topologies, in various species suggest that the mechanisms that govern the formation of tissues are conserved among species. To understand these mechanisms various models have been developed. In this thesis, we present a novel mechanical model for cell divisions and tissue for- mation. The model accounts for cell mechanics and cell-cell adhesion. In our model, each cell is treated individually, thus the changes in cell’s shape and its local rearrange- ments occur naturally as a response to the evolving cellular environment and cell-cell interactions. We introduce the processes of cell growth and divisions and numerically simulate tissue proliferation. As tissue grows starting from few cells, we follow the dynamics of the tissue growth and cell packing topologies. The outcomes are com- pared with experimental observations in Drosophila wing growth. Our model accounts for the exponential decay of the mitotic index and reproduces commonly observed cell packing topologies in proliferating epithelia. Next, we consider two biologically relevant division schemes, namely, division through asymmetric division plane and division by Hertwig’s rule. We study the im- pact of division planes on tissue growth and show that the division plane may affect cell packing topologies. Development of the tissue is accompanied by cellular rearrange- ments. We vary the extent of cellular rearrangements and analyse their effects on tissue topology. We find that when cells are allowed to move freely, more organized packing topologies emerge

Combined changes in Wnt signalling response and contact inhibition induce altered proliferation in radiation treated intestinal crypts

Curative intervention is possible if colorectal cancer is identified early, underscoring the need to detect the earliest stages of malignant transformation. A candidate biomarker is the expanded proliferative zone observed in crypts before adenoma formation, also found in irradiated crypts. However, the underlying driving mechanism for this is not known. Wnt signaling is a key regulator of proliferation, and elevated Wnt signaling is implicated in cancer. Nonetheless, how cells differentiate Wnt signals of varying strengths is not understood. We use computational modeling to compare alternative hypotheses about how Wnt signaling and contact inhibition affect proliferation. Direct comparison of simulations with published experimental data revealed that the model that best reproduces proliferation patterns in normal crypts stipulates that proliferative fate and cell cycle duration are set by the Wnt stimulus experienced at birth. The model also showed that the broadened proliferation zone induced by tumorigenic radiation can be attributed to cells responding to lower Wnt concentrations and dividing at smaller volumes. Application of the model to data from irradiated crypts after an extended recovery period permitted deductions about the extent of the initial insult. Application of computational modeling to experimental data revealed how mechanisms that control cell dynamics are altered at the earliest stages of carcinogenesis

How computational models can help unlock biological systems

AbstractWith computation models playing an ever increasing role in the advancement of science, it is important that researchers understand what it means to model something; recognize the implications of the conceptual, mathematical and algorithmic steps of model construction; and comprehend what models can and cannot do. Here, we use examples to show that models can serve a wide variety of roles, including hypothesis testing, generating new insights, deepening understanding, suggesting and interpreting experiments, tracing chains of causation, doing sensitivity analyses, integrating knowledge, and inspiring new approaches. We show that models can bring together information of different kinds and do so across a range of length scales, as they do in multi-scale, multi-faceted embryogenesis models, some of which connect gene expression, the cytoskeleton, cell properties, tissue mechanics, morphogenetic movements and phenotypes. Models cannot replace experiments nor can they prove that particular mechanisms are at work in a given situation. But they can demonstrate whether or not a proposed mechanism is sufficient to produce an observed phenomenon. Although the examples in this article are taken primarily from the field of embryo mechanics, most of the arguments and discussion are applicable to any form of computational modelling