Mechanochemical models for collective cell motility

At the tissue level, cells form a continuous sheet with no intercellular spaces. Dynamic behavior of these sheets is essential for tissue repair, organ formation in an embryo, and cancer metastasis. This dissertation explores mechanochemical models based on first principles to understand collective cell motility within epithelial layers. Specifically two situations are considered - morphogenesis in a Drosophila egg chamber, and dynamics of confluent monolayers on confined and unconfined geometries. During tissue elongation from stage 9 to stage 10 in Drosophila oogenesis, the egg chamber increases in length by about 1.7 fold. During these stages, spontaneous oscillations in the contraction of cell basal surfaces develop in a subset of follicle cells. This patterned activity is required for elongation of the egg chamber. However, the mechanisms generating these spatiotemporal patterns have been unclear. Here, we use a combination of quantitative modeling and experimental perturbation to show that mechanochemical interactions are sufficient to generate oscillations of myosin contractile activity in the observed spatiotemporal pattern. We propose that follicle cells in the epithelial layer contract against pressure in the expanding egg chamber. As tension in the epithelial layer increases, Rho-kinase signaling activates myosin assembly and contraction. The activation process is cooperative, leading to a limit cycle in the myosin dynamics. Our model produces asynchronous oscillations in follicle cell area and myosin content, consistent with experimental observations. In addition, we test the prediction that removal of the basal lamina will increase the average oscillation period. All together, the model demonstrates that in principle, mechanochemical interactions are sufficient to drive patterning and morphogenesis, independent of patterned gene expression. To model confluent monolayers on confined or unconfined geometries, we use a vertex model, where each cell is modeled as a polygon and motion of its vertices is governed by forces arising from cell-cell friction, cell substrate friction, cell elasticity, pressure, surface tension, and intrinsic contractile forces due to molecular motors. Since contractility is an active process, we have a biochemical signaling network, which is a negative feedback loop, regulating the magnitude of contractile force based on cell perimeter change. Collective cell motility modeled this way, has the same density dependent average velocity and myosin levels as in experiments. Moreover, on ring substrates, cells show counter rotation at the inner and outer boundary at short time scales (a few hours) and vortex formation as seen in experiments. Methods to incorporate an active protrusive force, based on Rac signaling pathway and cell death and cell division are underway. All in all, this model is a promising method to understand collective cell motility in a variety of conditions

Mechanochemical regulation of oscillatory follicle cell dynamics in the developing Drosophila egg chamber

During tissue elongation from stage 9 to stage 10 in Drosophila oogenesis, the egg chamber increases in length by ∼1.7-fold while increasing in volume by eightfold. During these stages, spontaneous oscillations in the contraction of cell basal surfaces develop in a subset of follicle cells. This patterned activity is required for elongation of the egg chamber; however, the mechanisms generating the spatiotemporal pattern have been unclear. Here we use a combination of quantitative modeling and experimental perturbation to show that mechanochemical interactions are sufficient to generate oscillations of myosin contractile activity in the observed spatiotemporal pattern. We propose that follicle cells in the epithelial layer contract against pressure in the expanding egg chamber. As tension in the epithelial layer increases, Rho kinase signaling activates myosin assembly and contraction. The activation process is cooperative, leading to a limit cycle in the myosin dynamics. Our model produces asynchronous oscillations in follicle cell area and myosin content, consistent with experimental observations. In addition, we test the prediction that removal of the basal lamina will increase the average oscillation period. The model demonstrates that in principle, mechanochemical interactions are sufficient to drive patterning and morphogenesis, independent of patterned gene expression

Cell density and actomyosin contractility control the organization of migrating collectives within an epithelium

The mechanisms underlying collective migration are important for understanding development, wound healing, and tumor invasion. Here we focus on cell density to determine its role in collective migration. Our findings show that increasing cell density, as might be seen in cancer, transforms groups from broad collectives to small, narrow streams. Conversely, diminishing cell density, as might occur at a wound front, leads to large, broad collectives with a distinct leader–follower structure. Simulations identify force-sensitive contractility as a mediator of how density affects collectives, and guided by this prediction, we find that the baseline state of contractility can enhance or reduce organization. Finally, we test predictions from these data in an in vivo epithelium by using genetic manipulations to drive collective motion between predicted migratory phases. This work demonstrates how commonly altered cellular properties can prime groups of cells to adopt migration patterns that may be harnessed in health or exploited in disease

Data on borrower behaviour collected from 349 female borrowers in AP and TS states

This is a primary data collected from face to face survey of 349 female borrowers, who are from SHGs in AP and TS states. The data comprises of demographic information as well as information on group dynamics and gender. The sampled borrowers belonged to four districts, namely Chittoor, Nalgonda, Srikakulam and Adilabad. The legend for the data is provided in sheet 3, while the names of the districts sampled are in sheet 2. The data was collected in 2014, post the split of erstwhile AP state into AP and Telangana states, and post the meltdown of MFI-promoted JLGs

Individual borrowing and default behaviour in surplus and constrained credit environments: evidence from India

The present article studies borrowing behaviour between credit surplus and credit constrained environments in the context of microfinance, with respect to rural borrowing. Surplus and constrained environments get defined based on the number of the state-promoted self help groups (SHGs) in the district, and the volume of credit disbursed through these SHGs. Four hundred nineteen respondents comprising of farmers, off-farm workers, farm labourers, small businesspersons, SHG members and chit-fund or cooperative members were interviewed in the surplus district of Chittoor and the constrained district of Nalgonda in the erstwhile state of Andhra Pradesh. Statistical analyses comprising of OLS, binary logistic regression, ANOVA, t-test and chi-square tests show that surplus environments offer more adverse credit terms, especially for farmers and farm labourers. Further, surplus causes over-borrowing and defaults. Constraint propels planned repayments. Both the environments offer varying credit terms across trades. We also observe better lending terms when farmers and traders are among lenders in a constraint environment. Interlinking factor markets like land, labour and capital in a constrained environment leads to efficient outcomes, reinforcing the theory of New Institutional Economics

Epithelial vertex models with active biochemical regulation of contractility can explain organized collective cell motility

Collective motions of groups of cells are observed in many biological settings such as embryo development, tissue formation, and cancer metastasis. To effectively model collective cell movement, it is important to incorporate cell specific features such as cell size, cell shape, and cell mechanics, as well as active behavior of cells such as protrusion and force generation, contractile forces, and active biochemical signaling mechanisms that regulate cell behavior. In this paper, we develop a comprehensive model of collective cell migration in confluent epithelia based on the vertex modeling approach. We develop a method to compute cell-cell viscous friction based on the vertex model and incorporate RhoGTPase regulation of cortical myosin contraction. Global features of collective cell migration are examined by computing the spatial velocity correlation function. As active cell force parameters are varied, we found rich dynamical behavior. Furthermore, we find that cells exhibit nonlinear phenomena such as contractile waves and vortex formation. Together our work highlights the importance of active behavior of cells in generating collective cell movement. The vertex modeling approach is an efficient and versatile approach to rigorously examine cell motion in the epithelium

Regulation of tissue morphodynamics: an important role for actomyosin contractility

Forces arising from contractile actomyosin filaments help shape tissue form during morphogenesis. Developmental events that result from actomyosin contractility include tissue elongation, bending, budding, and collective migration. Here, we highlight recent insights into these morphogenetic processes from the perspective of actomyosin contractility as a key regulator. Emphasis is placed on a range of results obtained through live imaging, culture, and computational methods. Combining these approaches in the future has the potential to generate a robust, quantitative understanding of tissue morphodynamics