Dystrophin restoration in resulted in significant improvements in cellular properties.
Dystrophin deficiency is linked to abnormalities in satellite cell behavior, including cell division and gene regulation.
Restoring dystrophin in muscle progenitor cells enhanced their ability to grow and develop into muscle cells.
The corrected muscle progenitor cells showed improved energy production and better resistance to stress.
In animal studies, the transplantation of corrected muscle progenitor cells was more effective in muscle repair.
These findings suggest that dystrophin is important for the function of muscle stem cells in .
Simplified
Although the lack of dystrophin expression in muscle myofibers is the central cause of (DMD), accumulating evidence suggests that DMD may also be a stem cell disease. Recent studies have revealed dystrophin expression in satellite cells and demonstrated that dystrophin deficiency is directly related to abnormalities in satellite cell polarity, asymmetric division, and epigenetic regulation, thus contributing to the manifestation of the DMD phenotype. Although metabolic and mitochondrial dysfunctions have also been associated with the DMD pathophysiology profile, interestingly, the role of dystrophin with respect to stem cells dysfunction has not been elucidated. In the past few years, editing of the gene that encodes dystrophin has emerged as a promising therapeutic approach for DMD, although the effects of dystrophin restoration in stem cells have not been addressed. Herein, we describe our use of a clustered regularly interspaced short palindromic repeats/Cas9-based system to correct the dystrophin mutation in dystrophic (mdx) (MPCs) and show that the expression of dystrophin significantly improved cellular properties of the mdx MPCs in vitro. Our findings reveal that dystrophin-restored mdx MPCs demonstrated improvements in cell proliferation, differentiation, bioenergetics, and resistance to oxidative and endoplasmic reticulum stress. Furthermore, our in vivo studies demonstrated improved transplantation efficiency of the corrected MPCs in the muscles of mdx mice. Our results indicate that changes in cellular energetics and stress resistance via dystrophin restoration enhance muscle progenitor cell function, further validating that dystrophin plays a role in stem cell function and demonstrating the potential for new therapeutic approaches for DMD. Stem Cells 2019;37:1615-1628.
Key numbers
20%
Increase in ATP Levels
Measured ATP levels in dystrophin-restored vs. control .
40%
Improved Cell Viability Under Hypoxia
Cell growth of dystrophin-restored vs. control under 1% O2.
0.6
Pax7+ Cells per Myofiber
Pax7+ cells per dystrophin-positive myofiber vs. control myofibers.
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