Author:

Abstract:

Myopathies are characterized by muscular weakness and impaired functionality caused by genetic and acquired factors. Muscular Dystrophies (MD) are amongst the most common diseases of the skeletal muscle 2 . MDs are marked by a progressive muscular degeneration, which leads patients to physical disability and shortens life expectancy. No curative treatment is currently available for MDs. Treatment with glucocorticoids and intensive physiotherapy can only alleviate the symptoms and partially delay the progression. A promising approach relies on stem cell therapy. However, issues such as limited availability, control of cell fate and paracrine effects on the host tissue need to be addressed before therapeutic applications may become feasible. Stem cell therapy with donor mesoangioblasts (MABs- vessels associated stem cells) has produced dramatic amelioration in dystrophic mice and dogs 3,4. Recently, induced pluripotent stem cells (iPSCs) have been generated from MABs (MAB-iPSCs). MAB-iPSCs reproduce unique features of pluripotent stem cells, still retaining a biased epigenetic memory towards the myogenic lineage. Interestingly, MAB-iPSC-derived mesodermal progenitors (MiPs) can be used for combined treatment of both skeletal and cardiac muscles in dystrophic mice 5. More recently, human MiPs have been derived and characterized although questions about their in vivo performance remained unanswered. During the current phd training we investigated the in vivo capacity of human MiPs, mainly focusing our attention on their skeletal myogenic commitment. We assessed the translational potential of human MiPs in dystrophic mice. Next, we compared the transcriptional profiles of human fibroblast-derived - and MAB-MiPs, and the miRNAs profile in order to predict a miRNA cocktail functional for increasing the myogenic commitment of the progenitors. In a second part of the project we wished to move forward with a novel therapeutic approach for enhancing muscle regeneration bypassing the use of stem cells. In this light exosomes have been increasingly studied and applied in regenerative medicine fields as delivery methods for tissue regeneration. Therefore we screened the content of exosomes derived from hypertrophic and dystrophic mice and we focused once again on their micro RNA signature with the goal of modulating muscle degenerative diseases in vivo.