Gerli, MFM;
(2016)
Lineage Plasticity and Regenerative Potential of Adult Muscle Stem Cells: Investigation of Satellite Cell Direct-Reprogramming and Pericyte Self-Renewal.
Doctoral thesis , UCL (University College London).
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Abstract
Satellite cells are responsible for most of adult skeletal muscle regeneration. Upon activation they differentiate into transient amplifying myoblasts that undergo cell fusion to form multinucleated fibres. Despite their remarkable differentiation ability and the positive outcomes obtained with transplantation in dystrophic mice and recently in patients with oculo-pharyngeal muscular dystrophy (OPMD), clinical trials in patients with Duchenne muscular dystrophy (DMD) showed limited efficacy, mainly ascribed to myoblasts low survival and poor migration ability. Muscle pericyte-derived mesoangioblasts (perivascular cells associated to the capillaries) also contribute to muscle regeneration and colonise the satellite cell niche. These cells can be injected systemically and migrate through the vascular endothelium, circumventing the necessity of multiple intra-muscular injections. Mesoangioblasts have been also tested in a recently completed phase I / II clinical trial to assess their safety profile in five DMD patients (EudraCT no. 2011-000176-33). We hypothesise that exploiting the key properties of myoblasts and mesoangioblasts may have the potential to produce clinically relevant cells, superior to those currently available. This work shows that exposure to molecules involved in pericyte specification such as the Notch ligand DLL4 and the growth factor PDGF-BB can induce direct reprogramming of primary satellite cells to pericyte-like cells. Reprogrammed cells acquire perivascular marker expression without losing the satellite cell marker Pax7. These highly myogenic cells can be expanded in culture and showed increased engraftment. In vitro and in vivo experiments also showed improved migration ability, similar to what has been observed with mesoangioblasts. Additionally, this thesis includes a set of experiments aiming to assess the self-renewal potential of mesoangioblast-derived cells via serial transplantation assays. Overall, the results obtained improve our understanding of smooth / skeletal fate choice and self-renewal, providing evidence of the possibility of exploiting a direct reprogramming approach to allow systemic delivery of myoblasts for cell therapies of muscular dystrophies.
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