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Stem cell binding to the endothelium during extravasation


Project Description

In a previous clinical trial carried out by the team (Cossu et al. 2015), HLA-matched, donor mesoangioblasts (pericyte-derived myogenic progenitors) were infused intra-arterially to patients with Duchenne muscular dystrophy. Beside safety, the trial aimed at measuring whether mesoangioblasts would engraft, and act as progenitors for healthy muscle cells, producing. dystrophin and hopefully ameliorating dystrophy. However mesoangioblasts were not recruited as expected from data in pre-clinical models (Sampaolesi et al. 2006). Therefore in a classic “bed to bench” approach, experiments are being conducted to implement the protocol and thus enhance engraftment. One major aim focuses on improving binding of mesoangioblasts to the endothelium, for example by studying how steroids, by reducing inflammation, reduce binding. The project will focus on this specific topic. It will involve a cell based perfusion assay using the IBIDI pump system that has been already set up and previously generated data. Using a monolayer of HUVEC cells, blood vessel conditions will be mimicked, and the binding of mesoangioblasts will be quantified at the single cell level, under different conditions.

Specifically the following will be studied:
1. Pre-treatment of mesoangioblasts with different growth factor and cytokines (e.g. SDF1, bFGF, HGF)
2. Treatment of the endothelium with different inflammatory and anti-inflammatory molecules (TNF, IL6, Steroids)
3. Interaction with leukocytes and comparison of the relative binding mechanisms, by using blocking antibodies.
4. In vivo experiments (intra-arterial injection) under selected experimental condition will validate the in vitro observation.
The project will lead to a better understanding of the mechanisms through which cells other than leukocytes, can bind to and cross the vessel wall. This will lead to implementation of the current cell therapy protocol used in patients.

The candidate will be trained in mammalian primary cell cultures, basic techniques of cell and molecular biology, basic animal surgery, time lapse and confocal microscopy, data analysis and experimental planning. They will get an understanding of pre-clinical work and clinical translation.

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with experience in cell and molecular biology and with an interest in regenerative medicine are encouraged to apply.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor ().

References

1. Cossu et al. 2015. Intra-arterial transplantation of HLA-matched mesoangioblasts in DMD. EMBO Mol. Med. 7, 1513.
2. Tedesco & Cossu. 2012. Stem cell therapies for muscle disorders. Curr. Op. Neurol. 25:597-603.
3. Tedesco et al. 2012. Transplantation of Genetically Corrected Human iPSC-Derived Progenitors in Mice with Limb-Girdle Muscular Dystrophy. Science Translational Medicine 4:140ra89.
3. Gargioli et al. 2008 PlGF-MMP9 expressing cells restore microcirculation and efficacy of cell therapy in old dystrophic mice. Nature Medicine 14:973-8.
4. Sampaolesi et al. Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature 444, 574.
Sampaolesi et al. 2003. Cell therapy of alpha sarcoglican null dystrophic mice trhough intra-arterial delivery of mesoangioblasts. Science 301, 487.

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