17 research outputs found
Interfollicular Epidermal Homeostasis: A Response to Ghadially, ‘25 Years of Epidermal Stem Cell Research’
Quantitative 3D analysis of complex single border cell behaviors in coordinated collective cell migration
Understanding the mechanisms of collective cell migration is crucial for cancer metastasis, wound healing and many developmental processes. Imaging a migrating cluster in vivo is feasible, but the quantification of individual cell behaviours remains challenging. We have developed an image analysis toolkit, CCMToolKit, to quantify the Drosophila border cell system. In addition to chaotic motion, previous studies reported that the migrating cells are able to migrate in a highly coordinated pattern. We quantify the rotating and running migration modes in 3D while also observing a range of intermediate behaviours. Running mode is driven by cluster external protrusions. Rotating mode is associated with cluster internal cell extensions that could not be easily characterized. Although the cluster moves slower while rotating, individual cells retain their mobility and are in fact slightly more active than in running mode. We also show that individual cells may exchange positions during migration
Toward a Systems Understanding of Signaling Pathway Function
A small number of developmental signaling pathways are used repeatedly throughout development in many different contexts. How these pathways interact with each other and the specific cell context to generate a wide range of appropriate responses remains an important question. The application of genomic and proteomic approaches and imaging at high spatiotemporal resolution are providing answers to this question and revealing new levels of complexity. Here, we discuss pathways as complex networks and examples of how signaling outcomes can be influenced by the temporal nature of the signal, its spatial regulation, and the cell context
Epithelial Stem Cells: Making, Shaping and Breaking the Niche
Epithelial stem cells maintain tissues throughout adult life and are tightly regulated by their microenvironmental niche to balance cell production and loss. These stem cells have been studied extensively as signal-receiving cells, responding to cues from other cell types and mechanical stimuli that comprise the niche. However, studies from a wide range of systems have identified epithelial stem cells as major contributors to their own microenvironment either through producing niche cells, acting directly as niche cells or regulating niche cells. The importance of stem cell contributions to the niche is particularly clear in cancer, where tumour cells extensively remodel their microenvironment to promote their survival and proliferation
Mechanism of murine epidermal maintenance: Cell division and the voter model
This paper presents an interesting experimental example of voter-model
statistics in biology. In recent work on mouse tail-skin, where proliferating
cells are confined to a two-dimensional layer, we showed that cells proliferate
and differentiate according to a simple stochastic model of cell division
involving just one type of proliferating cell that may divide both
symmetrically and asymmetrically. Curiously, these simple rules provide
excellent predictions of the cell population dynamics without having to address
their spatial distribution. Yet, if the spatial behaviour of cells is addressed
by allowing cells to diffuse at random, one deduces that density fluctuations
destroy tissue confluence, implying some hidden degree of spatial regulation in
the physical system. To infer the mechanism of spatial regulation, we consider
a two-dimensional model of cell fate that preserves the overall population
dynamics. By identifying the resulting behaviour with a three-species variation
of the "Voter" model, we predict that proliferating cells in the basal layer
should cluster. Analysis of empirical correlations of cells stained for
proliferation activity confirms that the expected clustering behaviour is
indeed seen in nature
The Ordered Architecture of Murine Ear Epidermis Is Maintained by Progenitor Cells with Random Fate
SummaryTypical murine epidermis has a patterned structure, seen clearly in ear skin, with regular columns of differentiated cells overlying the proliferative basal layer. It has been proposed that each column is a clonal epidermal proliferative unit maintained by a central stem cell and its transit amplifying cell progeny. An alternative hypothesis is that proliferating basal cells have random fate, the probability of generating cycling or differentiated cells being balanced so homeostasis is achieved. The stochastic model seems irreconcilable with an ordered tissue. Here we use lineage tracing to reveal that basal cells generate clones with highly irregular shapes that contribute progeny to multiple columns. Basal cell fate and cell cycle time is random. Cell columns form due to the properties of postmitotic cells. We conclude that the ordered architecture of the epidermis is maintained by a stochastic progenitor cell population, providing a simple and robust mechanism of homeostasis.Author Audi
Kinetics of cell division in epidermal maintenance
The rules governing cell division and differentiation are central to
understanding the mechanisms of development, aging and cancer. By utilising
inducible genetic labelling, recent studies have shown that the clonal
population in transgenic mouse epidermis can be tracked in vivo. Drawing on
these results, we explain how clonal fate data may be used to infer the rules
of cell division and differentiation underlying the maintenance of adult murine
tail-skin. We show that the rates of cell division and differentiation may be
evaluated by considering the long-time and short-time clone fate data, and that
the data is consistent with cells dividing independently rather than
synchronously. Motivated by these findings, we consider a mechanism for cancer
onset based closely on the model for normal adult skin. By analysing the
expected changes to clonal fate in cancer emerging from a simple two-stage
mutation, we propose that clonal fate data may provide a novel method for
studying the earliest stages of the disease