Biomechanics of the Eukaryote Cell

Lead Research Organisation: University of Cambridge
Department Name: Engineering

Abstract

The responses of cells are strongly dependent on their mechanical and chemical environment: in-vitro experiments with controlled substrate stiffness, topology and patterning of ligands have shown strong dependence of observables such as cell shape, area, shape and cytoskeletal protein arrangements on the substrates. However, these observables typically exhibit significant variability between nominally identical experiments though the statistics such as means and standard deviations of cell area, shape etc. over a large number of experiments is very consistent. This variability is not only inherent in terms of the bio-chemical processes occurring within cells but also critical to their functionality. However, deterministic "cell mechanics" models neglect/ignore these critical phenomena. In order to redress this deficiency an alternative approach has recently been developed wherein a statistical mechanics viewpoint is employed in the analysis of the response of cells.

The aim of the PhD will be to further develop and extend such modelling approaches by joining the scientific experiences in mathematical and computational modelling of biological media. Specifically, the aims will be:
-Extend the approach to a non-equilibrium setting so as to be able to model motility and invasion of single cells into tissues via adhesive type mechanisms.
-The framework has currently only been developed and used to analyse single cells. Extend the framework to multiple cells.
-Combine the first steps to develop a framework to model the collective motion of cells. This will first include the analysis of the migration of monolayers of cells.
-Introduce novel quantitative observables of collective and emerging phenomena.

Publications

10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509620/1 01/10/2016 30/09/2022
1946993 Studentship EP/N509620/1 01/10/2017 30/09/2020 Alberto Ippolito
 
Description The evolution of single cell observables, such as cell area, shape and cytoskeletal arrangements are strongly influenced by substrate properties. These observables not only exhibit significant variability in identical experiments, but their evolution rates are governed by distinct timescales. Timescales are critical to both cell functionality and purpose from the early stages of morphogenesis to the entire duration of the lifetime of the human body. During this PhD, we have designed a computational single cell model, a synthetic cell, and implemented it in different biological conditions. The synthetic cell uses a non-equilibrium formulation to yield the time evolution of all the before mentioned observables as well as cell motion. Remarkably, on an unpatterned rigid substrate, the synthetic cell behaviour is in excellent agreement with in-vitro cell tested in the identical conditions. In particular, the synthetic cell captures the different timescales governing cell morphology: an initial fast spreading and a slower delayed elongation. Additionally, using the synthetic cell, we predicted the effect of confinement, i.e. micropatterned adhesive stripes, on the cell observable timescale. From these results and the analysis of the nature of the synthetic cell, we've been able to suggest a physical reason governing these different observable timescales.
Currently, we are using the synthetic cell to uncover and explore emerging phenomena caused by strong asymmetries in substrate properties. On one hand, we are investigating the effects of different stiffness and collagen levels on the cell evolution and motile patterns. The aim is to further develop and apply the synthetic cell to stiffness and collagen gradients to study the dynamics of durotaxis and chemotaxis, respectively. We are also collaborating with researchers from the University of Brescia to investigate opposing gradients using the synthetic cell. On the other hand, we are investigating the effects of geometric asymmetries of a two rectangle patch systems on single cell behaviour. The aim is to understand how simple topological differences in otherwise symmetric systems cause a net bias in cell motile patterns.
Exploitation Route The outcomes produced so far are viable in both an academic and non-academic setting. The current synthetic cell can be exploited not only to understand but also to help design or even substitute in-vitro experiments. In fact, the key details and observables recorded in these experiments, such as cell motion, morphological changes and protein distributions, are all time dependent outputs of the model. Hence, from an academic perspective, the synthetic cell can be exploited to unveil emerging phenomena from novel substrate properties. Already the synthetic cell is being used by a different group of the University of Brescia to study competing gradients. Additionally, the same methods used to design and tailor the model can be expanded from single cells to larger biological masses. For example, a similar non-equilibrium approach can be adapted to tissue monolayers and then used to investigate the timescales governing collective behaviours. Outside academia, the synthetic cell could be further advanced to optimise the surfaces used for medical devices in healthcare. For example, the synthetic cell can assess the viability of a novel bone implant in terms of how readily cells invade the prosthesis.
Overall, whether the scope is to unveil novel emerging phenomena or to design or optimise a surface, the synthetic cell produced during this PhD is a step towards understanding the very complex dynamics that govern life.
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology