On the mechanism of wing size determination in fly development

Contact-inhibition of proliferation constrains epithelial tissue growth, and the loss of contact-inhibition is a hallmark of cancer cells. In most physiological scenarios, cell-cell contact inhibits proliferation in the presence of other growth-promoting cues, such as soluble growth factors (GFs). How cells quantitatively reconcile the opposing effects of cell-cell contact and GFs, such as epidermal growth factor (EGF), remains unclear. Here, using quantitative analysis of single cells within multicellular clusters, we show that contact is not a ''master switch'' that overrides EGF. Only when EGF recedes below a threshold level, contact inhibits proliferation, causing spatial patterns in cell cycle activity within epithelial cell clusters. Furthermore, we demonstrate that the onset of contactinhibition and the timing of spatial patterns in proliferation may be reengineered. Using micropatterned surfaces to amplify cell-cell interactions, we induce contact-inhibition at a higher threshold level of EGF. Using a complementary molecular genetics approach to enhance cell-cell interactions by overexpressing E-cadherin also increases the threshold level of EGF at which contact-inhibition is triggered. These results lead us to propose a state diagram in which epithelial cells transition from a contact-uninhibited state to a contact-inhibited state at a critical threshold level of EGF, a property that may be tuned by modulating the extent of cell-cell contacts. This quantitative model of contact-inhibition has direct implications for how tissue size may be determined and deregulated during development and tumor formation, respectively, and provides design principles for engineering epithelial tissue growth in applications such as tissue engineering.cancer ͉ contact inhibition ͉ development ͉ proliferation ͉ tissue engineering

Section: Resultssupporting

confidence: 52%

Tunable interplay between epidermal growth factor and cell–cell contact governs the spatial dynamics of epithelial growth

Kim¹,

Kushiro

Graham

et al. 2009

“…As in other cell models (23,25,26), we associate an energy with cell-cell contacts, where the energy is proportional to the surface area of contact between cells: W ad ¼ ðΓ∕2ÞP C , where P C is the surface area (perimeter in 2D) in contact with other cells. In addition, the response of single cells to low-frequency pressures and forces can be characterized by a cortical tension (23,26,27): W cort ¼ βP T where P T is the total surface area of a cell.…”

Section: Resultsmentioning

confidence: 99%

Coaction of intercellular adhesion and cortical tension specifies tissue surface tension

Manning

Foty²,

Steinberg

et al. 2010

374

349

In the course of animal morphogenesis, large-scale cell movements occur, which involve the rearrangement, mutual spreading, and compartmentalization of cell populations in specific configurations. Morphogenetic cell rearrangements such as cell sorting and mutual tissue spreading have been compared with the behaviors of immiscible liquids, which they closely resemble. Based on this similarity, it has been proposed that tissues behave as liquids and possess a characteristic surface tension, which arises as a collective, macroscopic property of groups of mobile, cohering cells. But how are tissue surface tensions generated? Different theories have been proposed to explain how mesoscopic cell properties such as cell-cell adhesion and contractility of cell interfaces may underlie tissue surface tensions. Although recent work suggests that both may be contributors, an explicit model for the dependence of tissue surface tension on these mesoscopic parameters has been missing. Here we show explicitly that the ratio of adhesion to cortical tension determines tissue surface tension. Our minimal model successfully explains the available experimental data and makes predictions, based on the feedback between mechanical energy and geometry, about the shapes of aggregate surface cells, which we verify experimentally. This model indicates that there is a crossover from adhesion dominated to cortical-tension dominated behavior as a function of the ratio between these two quantities.differential adhesion hypothesis | differential interfacial tension hypothesis | mathematical modeling | cell aggregate geometry | self-assembly I t is well established that many tissues behave like liquids on long timescales. Cell tracking in vivo and in vitro highlights (i) largescale flows, (ii) exchange of nearest neighbors in a cellular aggregate, and (iii) rounding-up and fusion of aggregates (1). Macroscopic rheological properties such as surface tension can be measured using a tissue surface tensiometer (TST) (1-8) or micropipette aspiration (9), and surface tension can be used to explain tissue self-organization in embryogenesis (8, 10-12) or cancer (13,14). In particular, cell sorting and tissue spreading can be explained in terms of tissue surface tensions that differ among cell types (1, 3-5, 8, 15, 16).A full understanding of tissue surface tension as a driving force for biological processes is important, and knowledge of its cellular origins would allow us to intelligently design drugs and treatments to alter tissue organization. Two opposing theories about the mesoscopic origin of tissue surface tension have coexisted over the last 30 years. One, the differential adhesion hypothesis (DAH), postulates that in analogy to ordinary fluids, tissue surface tension is proportional to the intensity of the adhesive energy between the constituent cells, which are treated as point objects. The DAH has proven successful in a variety of studies with cell lines (2-5, 15) , malignant (13, 14) and embryonic tissues (1,5,8,16) and is widely accepted (12...

“…To illustrate our interpretation of the observed interplay between cellular growth, motility and colony expansion, we formulate and analyze a simple growth model for adherent epithelial tissues. We choose as a point of departure a one dimensional version of the "vertex model" (47,50) as depicted in Fig. 5A.…”

Section: Resultsmentioning

confidence: 99%

Collective and single cell behavior in epithelial contact inhibition

Puliafito

Hufnagel

Neveu

et al. 2012

Self Cite

427

473

Control of cell proliferation is a fundamental aspect of tissue physiology central to morphogenesis, wound healing, and cancer. Although many of the molecular genetic factors are now known, the system level regulation of growth is still poorly understood. A simple form of inhibition of cell proliferation is encountered in vitro in normally differentiating epithelial cell cultures and is known as "contact inhibition." The study presented here provides a quantitative characterization of contact inhibition dynamics on tissuewide and single cell levels. Using long-term tracking of cultured Madin-Darby canine kidney cells we demonstrate that inhibition of cell division in a confluent monolayer follows inhibition of cell motility and sets in when mechanical constraint on local expansion causes divisions to reduce cell area. We quantify cell motility and cell cycle statistics in the low density confluent regime and their change across the transition to epithelial morphology which occurs with increasing cell density. We then study the dynamics of cell area distribution arising through reductive division, determine the average mitotic rate as a function of cell size, and demonstrate that complete arrest of mitosis occurs when cell area falls below a critical value. We also present a simple computational model of growth mechanics which captures all aspects of the observed behavior. Our measurements and analysis show that contact inhibition is a consequence of mechanical interaction and constraint rather than interfacial contact alone, and define quantitative phenotypes that can guide future studies of molecular mechanisms underlying contact inhibition.EMT | growth regulation | mechanics | mitosis