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Identifying mechanisms regulating collective migration of embryonic progenitor cells

Primary Supervisor: Dr Michael Smutny, Warwick Medical School

Secondary supervisors: Professor Mohan Balasubramanian & Dr Darius Koester

PhD project title: Identifying mechanisms regulating collective migration of embryonic progenitor cells

University of Registration: University of Warwick

Project outline:

    Background

    Collective cell migration plays a fundamental role during development in the embryo and wound healing in adults, and is also a hallmark of invasive cancer cells [1]. Collective behaviour is regulated by physical (cell-cell contacts) and chemical crosstalk between individually migrating cells, as well as external (mechanical/chemical) signals from the surrounding environment. To migrate efficiently through a complex 3D microenvironment in the developing embryo, cells typically self-organize into a cohesive cluster, which often consists of leader cells at the front and follower cells at the rear of the group [2].

    A highly conserved event during early vertebrate development is the specification and collective migration of mesendoderm (ME) progenitor cells, which is essential for normal body axis formation and functional brain development. ME cells are derived from internalization during gastrulation and migrate as a cohesive group with high directionality along the future body axis of the embryo [3]. It is currently unknown what mechanisms are in place to steer this collective through the embryo.

    Objectives

    To understand essential mechanisms underlying collective cell behaviour, this project will focus on identifying key parameters of cell-cell and cell-microenvironment interactions that can influence cell behaviour and migration of ME progenitor cells [4,5]. Central aims of investigations are: whether neighbouring cells exert forces, whether migration occurs in confinement or non-confined, whether the surrounding is soft or rigid, what substrate adhesion is prevalent, the dynamics and topology of the environment, and how individual cells in the collective undergo fate specification decisions and cell segregation.

    To address these questions, you will use a combination of interdisciplinary methodologies from cell and developmental biology, biophysics, membrane biology and computational tools to quantitatively analyse observations in vivo in the zebrafish embryo and in vitro in 3D cell culture assays. Dry components include strategies and design of Crispr/Cas9-mediated targeted genome editing in zebrafish.

    References:

    1. Friedl P. et al. Nat Rev Mol Cell Biol. 2009; 10(7):445.
    2. Mayor R. et al. Nat Rev Mol Cell Biol. 2016; 17(2):97.
    3. Smutny M. et al. Nat Cell Biol. 2017; 19(4):306.
    4. Scarpa E. et al. J Cell Biol 2016; 212(2):143.
    5. Roca-Cusachs P. et al. Curr Opion Cell Biol. 2013; 25(5):543.

    BBSRC Strategic Research Priority: Understanding the Rules of Life: Stem Cells

    Techniques that will be undertaken during the project:

    • Zebrafish and embryo work: generation of transgenic and knockout lines, microinjections, transplantation assays
    • Live cell imaging and fixed specimen: spinning disc, confocal and multiphoton microscopy, TIRF microscopy
    • Genomic editing using Crispr/Cas9
    • In vitro reconstitution of progenitor cells, 3D cell culture system, cells on supported lipid bilayers
    • Computational image analysis and statistics: Fiji, Matlab, R
    • Biophysical tools: laser ablation, microplate and confiner, microstretch device

    Typical pattern of working hours:

    • 37.5 hrs per week with flexible working arrangements

    Contact: Dr Michael Smutny, University of Warwick