Investigation of mechanisms of neuroprotective oxidative stress response induction by mesenchymal stem cell extracellular vesicles using human pluripotent stem cell resources at University of Edinburgh on FindAPhD.com

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Dr P De Sousa, Dr T Wishart No more applications being accepted Competition Funded PhD Project (European/UK Students Only)

Edinburgh United Kingdom

About the Project

Adult-tissue derived mesenchymal stem cells (MSC) and derivative extracellular vesicles (EV) attenuate neuroinflammation, and elicit neuroprotective oxidative stress response in animal and cell models of neurodegenerative diseases and injury. These are being clinically investigated as transplantable therapeutics for treatment of cognitive decline leading to dementia.

Heme oxygenase-1 (Hmox-/HO-1) is an inducible endoplasmic reticulum enzyme which oxidizes pro-oxidant heme to oxygen-free radical scavenging biliverdin. It is expressed throughout the brain, increasing with ageing and in degeneration affected regions. Its promoter contains an array of stress response elements that make it sensitive to induction by diverse pro-oxidant and inflammatory stimuli. MSC differentiated from a human embryonic stem cell (hESC) source provide a route to a more scalably renewable and standardisable therapeutic product and to discover the specific biomolecules responsible for their mode of action.

Using hESC-MSC derived by a patented method (EP1896569A1/US81104009/CA2599871) the project will evaluate the protective oxidative stress response inducing potential of derivative EV fractions from ambient oxygen and inflammatory cytokine modulated hESC-MSC. This will be assessed by administration to a human induced pluripotent stem cell (hiPSC) HO-1-mcherry reporter line differentiated into neuronal, glial and endothelial cells. EVs eliciting differential reporting and protection to an exogenous oxidative-stressing agent will be characterised at proteomic and RNA sequencing levels. Selected differentially expressed candidate biomolecules will be investigated in hiPSC-HO-1 target cells and an invertebrate drosophila models of neurodegenerative disease for necessity and sufficiency to elicit and sustain a oxidative stress protective response, the latter through epigenomic modifications mediated by oxygen sensing dioxygenases.

Funding Notes

This is part of a competition studentship with project 2020-CCBS-06 (see https://www.edinburghneuroscience.ed.ac.uk/project/dementia-including-alzheimers-disease-neurodegeneration-technology-advances/investigating). The best applicant will be offered the studentship, regardless of which project they wish to do. You can apply to both projects, but this will not offer any advantage.

The studentship includes a 3 year UKRI-level stipend, UK/EU level tuition fees, and an allowance for consumables and travel. The project would suit applicants with a background in Basic neuroscience, Informatics, Development, Regeneration. Essential Skills are: Tissue Culture and Microscopy.

References

M.A. de Godoy, et al (2018) Mesenchymal stem cells and cell-derived extracellular vesicles protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-beta oligomers, The Journal of biological chemistry, 293, 1957-1975.

Loboda A. et al (2016) Role of Rrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell. Bol. Life Sci 73: 3221-3247.

A method of differentiation to make multi-potent mesenchymal stem cells from pluripotent stem cells. Inventor: Paul De Sousa. Priority date of 3 March 2005, Granted and maintained in Europe (EP1896569), the US (US81104009) and Canada (CA2599871).

Llavero Hurtado M, Fuller HR, Wong AMS, Eaton SL, Gillingwater TH, Pennetta G, Cooper JD, Wishart TM. Proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo. Sci Rep. 2017 Sep 29;7(1):12412.

Koutsouraki E., Pells S., De Sousa, P.A.* (2019) Sufficiency of hypoxia inducible 2-Oxoglutarate dioxygenases to block chemical oxidative stress induced differentiation of human embryonic stem cells. Stem Cell Research 34, 101358

Where will I study?

University of Edinburgh

One of the world''s top universities, consistently ranked in the world top 50 and placed 20th in the QS World University Rankings 2020. We provide a stimulating working, learning and teaching environment with access to excellent facilities and attract the world''s best, from Nobel Prize winning laureates to future explorers, pioneers and inventors.

Investigation of mechanisms of neuroprotective oxidative stress response induction by mesenchymal stem cell extracellular vesicles using human pluripotent stem cell resources

University of Edinburgh College of Medicine and Veterinary Medicine