Cell streaming in cell monolayers approaching a glass-like state

Neighbor rearrangements between cells in biological tissue are essential to a host of processes, including embryonic development, tissue repair, and cancer progression. Often, they occur via positional swaps between cells, called T1 transitions, which act as the basic unit of movement of cells in close-packed tissues. Unlike T1 exchanges in the non-living matter such as foams, granular materials, and colloids, the T1 transitions in tissues cannot occur instantaneously due to the time required to remodel complex structures at cell-cell junctions. How this biological constraint affects the local mechanics of cells to collective behaviors inside tissues is not known. I recently used theoretical modeling and simulations, to demonstrate that cell-level control of time hindrance of the T1 transitions has potentially unique consequences that change the ways cells mechanically interact, collectively organize, and migrate.

Using an expanded version of the DVM, I showed that in the absence of time constraint on T1 transitions, the tissue undergoes a transition from a liquid-like state to a glassy solid-like state with lowering single-cell speed. However, this liquid-to-glass transition gradually disappears as T1 transitions become hindered. As that happens, we also find that the tissue develops a population of mobile cells organized into stream-like patterns in the background of slow or completely static cells. We call this the “Active Streaming Glassy State” which has the classic hallmarks of cell streaming observed in invasive cancer tumors. Exploring the origins of this phenomenon, we discover that as the T1 time constraint grows the tissue develops optimally stable cell collectives that selectively undergo directionally polarized T1 transitions, and eventually morph into elongated cellular streams.

Please visit my recent paper in Physical Review X to learn more about the active streaming glassy state of epithelial cell monolayers. It will be cool to realize some of the predictions in this paper in experiments!

Epithelial unjamming in human lung tissue

I have used the DVM to describe the solid-to-fluid like transformation via the 'unjamming transition (UJT)' observed in human lung epithelial tissues. I predicted a mode of migratory emergence as the motility of a single cell becomes more and more persistent. This allows the cells activate a migratory mode that is very collective in nature where cells coordinate their motion with a large number of neighbors over last distances. The resultant migratory patterns resemble dynamical swirls many of which could form moving in different directions within the tissue. I used quantitative data analysis to extract cell shape metrics and swirl sizes from the experimental data on cultured human lung tissue to show that the mechanical origin of these swirls describes perfectly the unjamming transition. I also use DVM to study the mechanism of a very well known migratory mode via 'Epithelial-to-Mesenchymal Transition' or EMT and predicted that EMT occurs via a gradual decrease in tensions on the apical cell-cell junctions. My analsys established UJT as a new and alternative mechanism of collective cell migration in epithelial cell monolayers that is distinct from EMT. Recently, several instances of UJT have been identified/suggested as a migratory mechanism in ex-vivo breast tumor spheriods, ductal carcinoma confined in collagen matrices, tissues exposed to gamma radiation and developing fruity fly and zebrafish embryos.

Models of active composite cell surface

There is growing evidence that the surface of living cells behaves as an active membrane composite (1-5) whose composition is actively regulated by the mechanics of cotical actin and myosin. Consequently, molecules at the cell surface could be identified based on their interaction with cortical actin: passive molecules - which bind to actomyosin filaments and inert molecules - which do not. Based on this classification (4,5), our recent theoretical framework (5) shows how cortical actomyosin, as an active fluid, could drive segregation of passive molecules from inert molecules at multiple scales. The theory makes many qualitative predictions, including the existence of a novel active phase segregated state, even at temperatures higher than the equilibrium critical segregation temperature. This active phase segregated state exhibits properties very distinct from the conventional equilibrium segregated state. In particular, it shows strong fluctuation dominated phase ordering (FDPO), and intermittency, as in turbulence. We also extended this theoretical framework to address features of large scale actomyosin-based segregation of different cell surface molecules, observed using fluorescence-based experiments.

For more details check out my recent paper in Physical Review Letters.

Here are some schematic pictures of the model:

Agent-based simulations of actin and myosin minifilaments

The goal of the project is to develop an agent-based model of cortical actin and non-muscle myosin-II minifilaments to understand the dynamical patterning of actin both at the cell cortex and in reconstituted systems of actomyosin adhered to the supported bilayer (see Koster et al PNAS 2016). We are exploring the phase diagram of patterning as a function of filament length, concentration, activity and chain flexibility.

In particular, we discovered that the finite sizes of the biopolymers, often ignored in theoretical formulations, are extremely important to include. The steric interaction of these components are key to understanding the hierarchical organization of actin and myosin at the cell cortex. Our in-vitro experiments also support this prediction. To learn more about the hierarchical organization of actin, myosin and different membrane receptors at the cell cortex the recent papers from Claire Waterman's group on focal adhesions are good references.

PhD details

During my Ph.D. in Physical Chemistry, I worked on Staticstical mechanics of different solution-phase rate processes, like, orientational relaxation, solvation and effects of nanoscale confinement on the bulk-behaviours of such processes. I also worked on thermodynamics of Biomolecular Complexation and dynamical aspects of intramolecular long-range communication in biomacromolecules.

Thesis title: "Mean Field Theory and Computer simulations on Non-equilibrium Phenomena in Complex Chemical Systems". Here is a link to my thesis.

Advisor: Dr. J. Chakrabarti, S. N. Bose National Centre for Basic Sciences, Kolkata, India