Study of stem cell-endothelium interactions to understand and implement cell transplantation for muscular dystrophy.

Lead Research Organisation: University of Manchester
Department Name: School of Health Sciences


Duchenne muscular dystrophy (DMD) is characterized by progressive degeneration of skeletal and cardiac muscle, caused by mutations in the dystrophin gene which encodes for a large protein, linking the cytoskeleton to the plasma membrane; in its absence, muscle fibres undergo degeneration during contraction and are progressively replaced by scar and fat.

Many novel approaches have entered clinical experimentation but none has reached significant clinical efficacy. We completed a "first in man" cell therapy trial for DMD based upon intra-arterial delivery of HLA-matched donor Mesoangioblasts (Mabs) (Cossu et al. EMBO Mol Med 2015). Mabs are progenitor cells originating from pericytes of skeletal muscle (Dellavalle et al. Nat. Cell Biol. 2007). They have the ability of adhering to and crossing the vessel wall when delivered intra-arterially. This was the innovative aspect of this trial, preceded by positive results in murine and canine models of muscular dystrophy (Sampaolesi et al. Science 2003, Nature 2006; Tedesco et al. STM 2011). We observed safety but modest efficacy, probably due also to our poor understanding of the mechanisms governing the adhesion of donor cells onto an inflamed (dystrophic) endothelium and the way the cross both the endothelial wall and the surrounding perivascular connective tissue.

This project aims to develop an appropriate in vitro model to mimic these processes with the aim to optimise the variables that maximise the differential extravasation in diseased and in healthy tissues.

Planned Impact

Regenerative medicine aims to develop biomaterial and cell-based therapies that restore function to damaged tissues and organs. It is a priority of the University and the nation, and a central focus of the EPSRC challenge theme "Healthcare Technologies". It is also an MRC strategic priority, "Repair and replacement: to translate burgeoning knowledge in regenerative medicine into new treatment strategies". It is in recognition of the challenges associated with clinical translation of regenerative medicine that EPSRC, MRC, BBSRC and TSB jointly funded the £25m UK Regenerative Medicine Platform - UoM is a partner on all three funded national hubs: 'Engineering and exploiting the stem cell niche', 'Acellular technologies, 'Safety and efficacy'. Our Centre for Doctoral Training in Regenerative Medicine, and hub partnerships, will have major impact by delivering a cohort of highly training scientists and clinicians who can take regenerative medicine to the next level of therapeutic efficacy, and engage with these national hubs. This capability will enable the UK to retain its position as a world-leader in regenerative medicine.

Specific impacts include:

(i) Biomedical scientists, the UK regenerative medicine community and international colleagues
Major impact will be achieved by training our students in the scientific methods required to: understand how the microenvironment (niche) directs cells to remodel tissues; design (nano)materials that interact at a mechanical and biochemical level with cells and orient their behaviour; understand how inflammatory processes affect regeneration; translate this knowledge to patients.
Our students will have the outstanding opportunity of benefiting directly from, and contributing directly to all the national UK Regenerative Medicine Platform hubs.
Added value will be achieved through research collaborations and data/reagent sharing across the University of Manchester and the Manchester Academic Health Science Centre, nationally through the hubs, and internationally through our six world-leading doctoral centre partners.
The Centre's strong links with MIMIT (Manchester: Integrating Medicine and Innovative Technology; linked to CIMIT, Boston USA), which develops clinical solutions for tissue repair and related unmet clinical needs, and with the Manchester Collaborative Centre for inflammation Research, enable our students to develop new regenerative strategies that encompass inflammatory control.

(ii) Biopharma
The ability to direct the effective repair or regeneration of tissues is highly sought after by cell therapy/regenerative medicine/tissue engineering companies wishing to translate these discoveries to new therapeutic products, and to Biopharma to inform the design and delivery of niche-based biologics and MSC-based anti-inflammatory therapies. We have more than 30 industrial partners, attesting to the strength of our Centre plan.
Our students will be advised by the University of Manchester Intellectual Property (UMIP) in all aspects of commercialisation, e.g. selling/licensing of reagents, provision of research expertise, in-house assays/techniques, co-development of technologies or licensing of IP.

(iii) General Public
The Centre will be a powerful platform for the Centre students to inform the public about our regenerative medicine activities and therapeutic advances.
The students will write review articles for popular press and student science magazines; develop skills in communications and public engagement; participate in Manchester Science Week and internet fora; develop outreach materials to inform local, national and international audiences, and meet patient groups.


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Description I showed that anti-inflammatory drugs reduced the ability of muscle progenitor cells - called mesoangioblast - to interact with the endothelial wall of the veins. This is counter interacting with a mesoangioblast-based treatment which has been tested with a first and an ongoing clinical trial conducted by Prof. Giulio Cossu
I have started to investigate the biomolecular process behind mesoangioblast-endothelium interactions.
Exploitation Route I should finish the biomolecular mechanism characterization and get the same results through in vivo experiments
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology