Interface Contractility between Differently Fated Cells Drives Cell Elimination and Cyst Formation

Abstract

SummaryAlthough cellular tumor-suppression mechanisms are widely studied, little is known about mechanisms that act at the level of tissues to suppress the occurrence of aberrant cells in epithelia. We find that ectopic expression of transcription factors that specify cell fates causes abnormal epithelial cysts in Drosophila imaginal discs. Cysts do not form cell autonomously but result from the juxtaposition of two cell populations with divergent fates. Juxtaposition of wild-type and aberrantly specified cells induces enrichment of actomyosin at their entire shared interface, both at adherens junctions as well as along basolateral interfaces. Experimental validation of 3D vertex model simulations demonstrates that enhanced interface contractility is sufficient to explain many morphogenetic behaviors, which depend on cell cluster size. These range from cyst formation by intermediate-sized clusters to segregation of large cell populations by formation of smooth boundaries or apical constriction in small groups of cells. In addition, we find that single cells experiencing lateral interface contractility are eliminated from tissues by apoptosis. Cysts, which disrupt epithelial continuity, form when elimination of single, aberrantly specified cells fails and cells proliferate to intermediate cell cluster sizes. Thus, increased interface contractility functions as error correction mechanism eliminating single aberrant cells from tissues, but failure leads to the formation of large, potentially disease-promoting cysts. Our results provide a novel perspective on morphogenetic mechanisms, which arise from cell-fate heterogeneities within tissues and maintain or disrupt epithelial homeostasis.

Active Vertex Model for Cell-Resolution Description of Epithelial Tissue Mechanics

“…We conclude by noting that recently there have been several interesting attempts at extending the Vertex Model description to three dimensions [85,[107][108][109][110][111][112]. While in principle possible, extending the AVM to a curved surface or making it fully three-dimensional would be quite involved.…”

Influence of cell mechanics and proliferation on the buckling of simulated tissues using a vertex model

“…Instead, the latter is a function of the relative cortical expansion and its relative thickness (compared with the brain size). Moreover, we showed that the folding of simulated growing cell monolayers can occur without the presence of different types of cells as in Tamulonis et al (2011), Bielmeier et al (2016, or differential tension between the boundary (apical and basal) edges of the cells, as in Š torgel et al (2016), Höhn and Hallmann (2011). In our simulations, all the cells were identical and only characterised by their normalised overall contractility, adhesion to their neighbours and proliferation rate.…”

“…Tissue folding is a frequently observed phenomenon, from blastula gastrulation (Tamulonis et al 2011;Rauzi et al 2013;Polyakov et al 2014), to the formation of brain convolutions (Tallinen et al 2014(Tallinen et al , 2016, gut villis Shyer et al 2013), cyst (Bielmeier et al 2016) and even crocodile head scales (Milinkovitch et al 2013). However, the causes of tissue buckling and folding are not well understood.…”

“…Some studies suggest that buckling results from cell mechanical properties. Bielmeier et al (2016) demonstrated that buckling can emerge from interface contractility between differently fated cells, potentially leading to cyst formation. Tamulonis et al (2011) showed that the blastula gastrulation can emerge from the endoderm and ectoderm being characterised by different apical cell constriction and intercellular adhesion.…”

“…Among them, one can find the vertex models that were used in the past decade to study the mechanics of confluent cell monolayers (Alt et al 2017;Fletcher et al 2013Fletcher et al , 2014. Although 3D vertex models were recently proposed (Bielmeier et al 2016;Monier et al 2015;Misra et al 2016), the 2D models are commonly used to describe both in-plane tissues as seen from the apical face for the study of phenomena like cell sorting (Aliee et al 2012;Umetsu et al 2014) or wound healing (Nagai and Honda 2009), and to describe transverse crosssections of tissues for investigating phenomena that are three-dimensional in nature such as tissue folding (Štorgel et al 2016) and gastrulation (Tamulonis et al 2011;Rauzi et al 2013;Polyakov et al 2014).…”