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Project

Notch signaling and myogenic potential of human/murine somatic and pluripotent stem cells

Fate conditioning is a determining factor in regenerative medicine: driving cell commitment towards a tissue or another can expand the potential of stem cell injections and raise up repair efficiencies.
Fate discrimination between cardiac and skeletal muscle remains largely unsolved and fascinating: which molecular signals drive the commitment towards the two distinct muscle types, during embryogenesis or stem cell differentiation?
Our preliminary results, on bsarcoglycan knock-out (bsg-/-) dystrophic mice, showed us that cardiac mesoangioblasts, which are normally cardiac-committed, when isolated from dystrophic hearts, show impaired cardiac differentiation and a prominent skeletal programme, differentiating in vitro spontaneously into myotubes. First molecular characterizations linked this fate switch to alterations in Notch signalling and Mef2A/C/D patterns: ligand- or shRNA-based in vitro medium-conditioning allowed a partial governance of cell commitment towards cardiac or skeletal fate, both on dystrophic or wt cell lines.
So, my PhD project will be dedicated to deepen the study on Notch and Mef2 gene networks and interactions and to exploit this molecular model to characterize molecular signals, eligible for cell conditioning, in vitro and in vivo, towards cardiac or skeletal muscle. This approach has a direct clinical relevance: enhancing cell therapy efficiency and reliability for skeletal and cardiac muscle repair in dystrophic patients.
In order to exactly trace the two fates, skeletal or cardiac, a transgenic double-tracer (e.g. Gata4-GFP/MyoD-lacZ) mouse will be obtained and crossbred with our dystrophic bsg-/- mice: the dystrophic/double-tracer will be an important model to follow up and quantify the fate switch into precursors of cardiac or skeletal line, both in vitro and in vivo.    
 
 
Date:23 Mar 2009  →  22 Feb 2013
Keywords:Somatic stem cells
Project type:PhD project