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EASTBIO: Generating novel sources of stem cells for regenerative and anti-infective applications


College of Medicine and Veterinary Medicine

About the Project

Bacterial resistance to antibiotics is well recognised as a major threat to animal and human health and there is an urgent need to find alternatives to the generalized use of antibiotics. The aim of this project is to develop robust approaches for the application of mesenchymal stem/stromal cell (MSC) preparations, and their products (e.g. exosomes) as cell-free off-the-shelf products, for tissue regeneration applications, including as anti-infectives and to combat antimicrobial resistance (AMR).
Recent work [1,2], including from our laboratory [3], showed that MSCs and their conditioned media (CM/exosomes) can be used in the treatment of infection not only in animals, in multiple-drug resistant bacteria (MDR) in dogs and clinical bovine mastitis, but also in humans to treat GvHD, ARDS and Covid-19, and MDR tuberculosis.

Critically, one major draw-back in the development and application of robust MSC therapies is the limited lifespan of primary MSCs as well as their heterogeneity. Another limitation to the successful development of novel anti-infective approaches is the lack of physiologically-relevant ex-vivo models of infection for testing new therapies without the need to use experimental animals.

This project will aim to produce novel MSC lines and exosome cell-free-preparations from dog and other relevant large animal models towards the elucidation of the mechanisms underpinning MSCs regeneration and anti-microbial properties, and with a view to develop novel therapeutic cell-free products. The project will use cutting-edge in vitro technologies such as tissue organoid cultures (organoids are miniaturized versions of organs which resemble the physiology of the native tissue) to test and establish the properties of the MSC lines generated and their products. This investigation may also lead to the identification of novel MSC-derived factors which could provide advantages as cell-free therapeutic products compared to current available commercially MSC therapies.

This PhD project will have 3 main objectives;

1) To establish reversible immortalised MSC lines (iMSCs) from dogs and other large animal models as a source of defined cells.

2) To screen and select iMSC lines and exosome fractions with optimal anti-infective and tissue regeneration properties.

3) To assess the antibacterial and repair potential of MSC lines and exosome fractions selected in objective 2 using an ex-vivo organoid model of infection.

The student working in this project will build expertise in stem cell biology, organoid technology, microbiology and immunity. He/she will become proficient in a wide variety of cell and molecular biology techniques including genetic manipulation of mammalian cells, bacterial culture, MSCs and organoid culture, immunohistochemistry, enzyme-linked immunosorbent arrays, gene expression analyses by next-generation sequencing, qPCR, siRNA and CRISP-Cas9 gene editing.

Funding information and application procedures:
This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership (DTP) http://www.eastscotbiodtp.ac.uk/how-apply-0 .

EASTBIO Application and Reference Forms can be downloaded via http://www.eastscotbiodtp.ac.uk/how-apply-0

Please send your completed EASTBIO Application Form along with a copy of your academic transcripts to

You should also ensure that two references have been send to by the deadline using the EASTBIO Reference Form.


Funding Notes

This opportunity is open to UK and international students and provides funding covering stipend and UK level tuition fees. The University of Edinburgh covers the difference between home and international fees meaning that the EASTBIO DTP offers fully-funded studentships to all appointees. There is a cap on the number of international students the DTP recruits. It is important that we know from the outset which fees status category applicants fall under when applying to our university.

Please refer to UKRI (View Website ing-people-and-skills/find-studentships-and-doctoral-training/get-a-studentship-to-fund-your-doctorate/) and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria (View Website).


References

1. Leng Z, et al. (2020). Transplantation of ACE2(-) Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia. Aging Dis 11:216-228.
2. Johnson V, et al. (2017). Activated Mesenchymal Stem Cells Interact with Antibiotics and Host Innate Immune Responses to Control Chronic Bacterial Infections. Sci Rep 7:9575.
3. Cortes-Araya Y, et al. (2018). Comparison of Antibacterial and Immunological Properties of Mesenchymal Stem/Stromal Cells from Equine Bone Marrow, Endometrium, and Adipose Tissue. Stem Cells Dev 27:1518-1525.


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