Mesenchymal stem cells and their secreted exosomes exert therapeutic effects in Duchenne muscular dystrophy

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Conference Proceeding

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J Extracell Vesicles


Duchenne muscular dystrophy (DMD) is a progressive lethal, X-linked disease of skeletal and cardiac muscles caused by mutation of the dystrophin gene, which leads to muscle degeneration. Cell therapy using different cell types has been considered a potential therapeutic approach for the treatment of DMD. Mesenchymal stromal cells (MSCs) are obtained from autologous bone marrow and adipose tissues or from allogeneic placenta and umbilical cord. The safety and therapeutic impact of MSCs have been demonstrated in pre-clinical and clinical studies and are attributed to paracrine effects that are partly mediated by extracellular vesicles. Here, we studied the therapeutic effects of MSCs and their secreted exosomes using human in vitro disease models of skeletal muscle cultures derived from healthy and Duchenne patients and MDX mice. Treatment of satellite cells with conditioned media or exosomes secreted by MSCs increased the proliferation and generation of PAX7+/MyoD+ cells and the differentiation of human myoblasts from both healthy and DMD patients. MSCs from different sources exerted differential effects on the function of the muscle cells. Secretome and RNA sequencing analysis of the MSC-derived exosomes revealed specific cytokines and clusters of miRNAs and long non-coding RNAs that were associated with anti-inflammatory and pro-regenerative activities in muscle cells. Using novel quantitative miRNA reporters, we demonstrated that MSC-derived exosomes delivered both endogenous and exogenous miRNAs to satellite cells and myoblasts. Intramuscular implantation of MSCs to MDX mice resulted in decreased tissue fibrosis and CK level, increased differentiation of satellite cells, expression of utrophin and motor function. Imaging analyses using labelled MSCs and exosomes, demonstrated their localisation in the muscle tissues up to 4 weeks. These results demonstrate that MSCs and their secreted exosomes have important clinical applications in cell therapy of DMD partly via the targeted delivery of therapeutic non-coding RNAs.



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