Embryonic Vessel-Associated Progenitors in Skeletal Muscle Development and in Tissue Repair

Regeneration of skeletal muscle is sustained by production of new myofibers and satellite cells are indispensable for this process. However, a variety of non-satellite cell types can also participate in skeletal muscle regeneration in the adult. There is much interest in understanding the biology of these progenitors because of their potential use in clinical applications for degenerative diseases such as muscular dystrophies (MD). At the moment the best candidates are mesoangioblasts (MABs). Understanding the basic biology of these cells is mandatory to develop treatment to improve their regenerative potential. To unveil their native identity and physiological role, we used a lineage tracing strategy to label embryonic endothelial progenitors and we demonstrated that haemogenic endothelium harbors a population of progenitors that physiologically contributes to several mesodermal lineages during development, representing the in vivo counterpart of MABs. By following the fate of these cells until adulthood we showed that these cells contribute to subset of myogenic progenitors and take part in muscle regeneration. By using the same genetic system, we analyzed the effects of a pharmacological treatment based on a nitric oxide-donor on the fate of these cells during embryogenesis and during adult regeneration, showing an increased endothelial contribution to myogenesis in both cases. Moreover, combining current pre-clinical protocols for MABs transplantation with genetic manipulation, we demonstrated that over-expression of the MAGE protein Necdin promotes their survival and myogenic differentiation, resulting in an improved therapeutic efficacy.