Optimizing Proliferation of Muscle Stem Cells
Duchenne muscular dystrophy (DMD) is a pervasive and catastrophic condition concerned with skeletal muscle degeneration. There is presently no cure for DMD, but a promising avenue for novel therapies is inducing muscle regeneration via muscle stem cells. One specific target utilizing muscle stem cell approaches is the Notch signaling pathway, which governs cell proliferation, cell fate decision, and induction of differentiation. Additionally, inhibition of the Notch signaling pathway has been directly implicated in the pathogeny of DMD. The Notch pathway is well-characterized, however the difference in the proliferation of muscle stem cells promoted by the four different Notch receptors and five different ligands found in mammals has not been explicitly defined using direct comparisons in a single cell line. Here we show that certain Notch receptors and Notch ligands are more effective than others at activating the canonical Notch pathway. We found in luciferase assays that specific pairs of Notch ligands and receptors elicited greater activity of the Notch pathway by the Hes1-promoter-driving luciferase reporter gene. We anticipate our assays to be a starting point for more sophisticated translational studies. Future experiments should be done in muscle stem cells or in vivo in order to further generalize findings to DMD therapies. As the Notch pathway is a major target of novel therapies for DMD, a well-defined understanding of how various upstream components contribute to self-renewal, proliferation, and differentiation of muscle stem cells to regenerate skeletal muscle is crucial; with this knowledge, we can optimize novel therapies and combat skeletal muscle degeneration in DMD patients.