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Integrating mechanical and chemical cues in stem cell migration and division


   Faculty of Biology, Medicine and Health

  , ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Adult stem cells are found in most tissues, and the interaction between stem cells and their niche tightly controls their self-renewal and differentiation state. Furthermore, environmental factors can ‘activate’ stem cells leading to acquisition of a migratory phenotype, homing to specific sites and differentiation to mediate tissue maintenance and repair. The stem cell microenvironment consists of a myriad of physical and biochemical cues, and these are decoded by stem cells to produce the appropriate response. How these mechanical and chemical factors that control stem cells are integrated to control stem cell behaviour, however, is not known. 

We will use mesenchymal stem cells, which migrate and differentiate in a stereotypical manner in response to specific soluble factors, substrate mechanics and cytoskeletal tension, to understand signal integration. Combining cell biology approaches and state-of-the art microscopy (super resolution, FRET biosensors (Paul et al., 2015)) with mathematical modelling (Hetmanski et al., 2016, 2019, 2021) will allow us to understand signalling networks that govern division and migratory outcomes. We will further experimentally manipulate substrate rigidity, cell shape (using micropatterning) and the cytoskeleton to reveal their impact on intracellular signalling and inform mathematical models. This interdisciplinary approach will provide insight into stem cell behaviour and how it can be manipulated for application in tissue engineering.

1.     Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject.

2.     For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the PhD title.

3.     For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit www.internationalphd.manchester.ac.uk


Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website View Website
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website View Website

References

Hetmanski JHR, Jones MC, Chunara F, Schwartz JM, Caswell PT.
Combinatorial mathematical modelling approaches to interrogate rear retraction dynamics in 3D cell migration.
PLoS Comput Biol. 2021 Mar 10;17(3):e1008213. Hetmanski JHR, de Belly H, Busnelli I, Waring T, Nair RV, Sokleva V, Dobre O, Cameron A, Gauthier N, Lamaze C, Swift J, Del Campo A, Starborg T, Zech T, Goetz JG, Paluch EK, Schwartz JM, Caswell PT.
Membrane Tension Orchestrates Rear Retraction in Matrix-Directed Cell Migration.
Dev Cell. 2019 Nov 18;51(4):460-475.e10. doi: 10.1016/j.devcel.2019.09.006. Hetmanski JH, Zindy E, Schwartz JM, Caswell PT.
A MAPK-driven feedback loop suppresses Rac activity to promote RhoA-driven cancer cell invasion
PLOS Computational Biology (2016) May 3;12(5):e1004909.
doi: 10.1371/journal.pcbi.1004909. PMID: 27138333
Galarza Torre A, Shaw JE, Wood A, Gilbert HTJ, Dobre O, Genever P, Brennan K, Richardson SM, Swift J.
An immortalised mesenchymal stem cell line maintains mechano-responsive behaviour and can be used as a reporter of substrate stiffness.
Sci Rep. 2018 Jun 12;8(1):8981. doi: 10.1038/s41598-018-27346-9.
Swift J, Ivanovska IL, Buxboim A, Harada T, Dingal PC, Pinter J, Pajerowski JD, Spinler KR, Shin JW, Tewari M, Rehfeldt F, Speicher DW, Discher DE.
Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation.
Science. 2013 Aug 30;341(6149):1240104. doi: 10.1126/science.1240104.

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