Abstract
Cell populations in multicellular organisms show genetic and non-genetic heterogeneity, even in undifferentiated tissues of multipotent cells during development and tumorigenesis. The heterogeneity causes difference of mechanical properties, such as, cell bond tension or adhesion, at the cell–cell interface, which determine the shape of clonal population boundaries via cell sorting or mixing. The boundary shape could alter the degree of cell–cell contacts and thus influence the physiological consequences of sorting or mixing at the boundary (e.g., tumor suppression or progression), suggesting that the cell mechanics could help clarify the physiology of heterogeneous tissues. While precise inference of mechanical tension loaded at each cell–cell contacts has been extensively developed, there has been little progress on how to distinguish the population-boundary geometry and identify the cause of geometry in heterogeneous tissues. We developed a pipeline by combining multivariate analysis of clone shape with tissue mechanical simulations. We examined clones with four different genotypes within Drosophila wing imaginal discs: wild-type, tartan (trn) overexpression, hibris (hbs) overexpression, and Eph RNAi. Although the clones were previously known to exhibit smoothed or convoluted morphologies, their mechanical properties were unknown. By applying a multivariate analysis to multiple criteria used to quantify the clone shapes based on individual cell shapes, we found the optimal criteria to distinguish not only among the four genotypes, but also non-genetic heterogeneity from genetic one. The efficient segregation of clone shape enabled us to quantitatively compare experimental data with tissue mechanical simulations. As a result, we identified the mechanical basis contributed to clone shape of distinct genotypes. The present pipeline will promote the understanding of the functions of mechanical interactions in heterogeneous tissue in a non-invasive manner.
Highlights
There are intrinsic differences among cells within any population, even in genetically uniform populations such as, clonal populations of bacteria, yeasts, and undifferentiated plant and animal cells (Elowitz, 2002; Raser, 2004; Raj and van Oudenaarden, 2008; Eldar and Elowitz, 2010; Itzkovitz et al, 2011; Meyer and Roeder, 2014)
The emergence of cellular heterogeneity in epithelial tissues alters the morphology of the boundaries between neighboring populations and thereby affects the cellular geometry in the tissue
We calculated the circularity of each clone (Section Clone Shape Quantification; Figures 1C, 2), and Supplementary Figure S1)
Summary
There are intrinsic differences among cells within any population, even in genetically uniform populations such as, clonal populations of bacteria, yeasts, and undifferentiated plant and animal cells (Elowitz, 2002; Raser, 2004; Raj and van Oudenaarden, 2008; Eldar and Elowitz, 2010; Itzkovitz et al, 2011; Meyer and Roeder, 2014). In the context of the cell competition, known as the tissue homeostatic system, to eliminate unfit cells from heterogeneous populations (Vincent et al, 2013; Amoyel and Bach, 2014; Morata and BallesterosArias, 2015), the intermingling of cells at clonal boundaries facilitates the competition by increasing the contact length between competing genotypes, so-called winner and loser cells (Levayer et al, 2015; Levayer and Moreno, 2016) Those insights suggest the potential to predict physiological consequences (e.g., tumor malignancy) based on the quantification of clone shapes. The establishment of a pipeline that combines the quantification of clone shapes with an analysis of the physical mechanisms underlying the clone shapes would be beneficial
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