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Investigating the role of mechanical and environmental cues controlling the movement of macrophages

Principal Supervisor: Dr Darius Koester

Secondary Supervisor(s): Dr Aparna Ratheesh

University of Registration: University of Warwick

BBSRC Research Themes:

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Deadline: 4 January, 2024


Project Outline

Immune cells in our body have to navigate complex environments to find and counter pathogens or infected cells. To do so, immune cells comprise of fascinating shape-changing abilities to squeeze through tiny openings and can move through a variety of tissues using different modes of mobility. In addition to their role as our defence mechanism, some immune cells such as macrophages are also important in organogenesis during embryonic development and homeostasis in adults. Macrophages have the ability to deposit material along their path and pull and push cells of the developing tissues to induce locally events of differentiation.

While we have a good understanding of the chemical cues that are involved in guiding and activating immune cells, there is mounting evidence that physical properties of the environment also play an important role. Using the combined strengths of the Ratheesh and Köster labs, we want to decipher these biophysical cues directing macrophages using new, biophysical tools.

We have developed an in-vitro system that can mimic different cell surfaces for the study of cell-cell adhesion using TIRF microscopy. The aim of the project is to adapt and use this system to study macrophage migration using integrin or cadherin-based adhesion molecules. This will be combined with spatial confinement either by static micro-fabricated structures or by dynamic confinement, and with substrates of different stiffness. This novel approach will allow to distinguish between mechanical and biochemical cues that are usually mingled when observing cells in living organisms. To validate the findings, experiments on macrophage dynamics in living organisms will be performed using multi-photon excitation microscopy.

Fig1

References

Ghosh S, Köster DV (2023), Study of cell-cell adhesion formation and dynamics in cancer cells using a hybrid cell-lipid bilayer system, Biophysical Journal, doi: 10.1016/j.bpj.2022.11.1816

Blackley D, Cooper JH, Pokorska P, Ratheesh A (2021), Mechanics of developmental migration, Seminars in Cell & Developmental Biology, doi: 10.1016/j.semcdb.2021.07.002

Techniques

  • Mammalian and fly cell culture, cloning of protein constructs for expression in cells, western blots, immune-fluorescence.
  • Crossing and maintenance of fly lines.
  • Handling of lipids and preparation of supported lipid bilayers
  • Fluorescence microscopy techniques: widefield, TIRF, confocal, multi-photon excitation
  • Quantitative phase contrast imaging
  • Mechanical manipulation of cells, dynamic cell confiner
  • Quantitative image analysis