Investigating mesenchymal Stem/Stromal Cells-derived extracellular vesicles neuroprotection

Our goal is to harness the therapeutic use of stem cells to repair neuronal damage in the brain. It is our hypothesis that neuroprotective factors that are naturally present in our body, specifically released by mesenchymal stem cells via extracellular vesicles will reverse the effects of synaptic dysfunction, a well-established early mechanism of Alzheimer’s disease (AD) which contributes to pathology spreading in the brain over time.

Mesenchymal stem cells convey neuroprotective molecules by releasing extracellular vesicles, small particles that contain all kinds of factors e.g., lipids, proteins, nucleic acids etc. These extracellular vesicles enter the bloodstream and can easily reach targets far away from the original source, including the brain, and release their content there. Utilising comparative proteomics and digital transcriptomics, we have already isolated and characterised over twenty potential therapeutic candidate molecules (both proteins and miRNA), all demonstrating qualities that may mediate neuroprotection.

We now propose to validate these factors and understand how they concur to the mechanism mediating MSCs-EVs neuroprotection. Starting from in vitro AD models (e.g. based on primary mouse hippocampal neurons treated with amyloid-β) and “simple” live models of AD disease, the project will move to explore neuroprotection in iPSC neurons generated from AD patients and delivery in our new blood–brain barrier (BBB) in vitro

model. We will incorporate the neuroprotective factors in lipid nanobubbles containing MRI contrast agents as potential therapeutic vectors for crossing the BBB to the site of action. We will also explore more delivery systems aiming to bypass the BBB with targeted drug delivery.

The successful applicant will gain diverse training in molecular cell biology establishing stem cells from human cord tissues, extracellular vesicles isolation and induced pluripotent stem cell (iPSC)-culturing and differentiation. The PhD candidate will also experience working as part of a large interdisciplinary team. Studies will be supported by the School of Science and Technology at Nottingham Trent University, the 2023 Modern University of the Year (Times Higher Education). The successful applicant will have a first or a high 2.1 M-level qualification in bioscience and a keen interest and curiosity for the field. Prior proven experience in the research laboratory will be an advantage.

Supervisors

1) Elisabetta Verderio Edwards (DOS); email: elisabetta.verderio-edwards@ntu.ac.uk

2) Elisa Tonoli; email: elisa.tonoli@ntu.ac.uk

3) Gareth Cave; email: gareth.cave @ntu.ac.uk