Suppressing Hippo signaling in the stem cell niche promotes skeletal muscle regeneration

Our AAV9 Salvador shRNA strategy recreates a myofiber ‐guided regenerative stem cell niche and promotes simultaneous myogenesis and angiogenesis‐neovascularization for the functional recovery of skeletal muscles in ischemic extremities. These myofibers release paracrine elements to activate (a) satellite cells to proliferate and self‐renew for my ogenesis and (b) endothelial cells to stimulate angiogenesis and neovascularization. AbstractLack of blood flow to the lower extremities in peripheral arterial disease causes oxygen and nutrient deprivation in ischemic skeletal muscles, leading to functional impairment. Treatment options for muscle regeneration in this scenario are lacking. Here, we selectively targeted the Hippo pathway in myofibers, which provide architectural support for muscle stem cell niches, to facilitate functional muscle recovery in ischemic extremities by promoting angiogenesis, neovascularization, and myogenesis. We knocked down the core Hippo pathway component, Salvador (SAV1), by using an adeno ‐associated virus 9 (AAV9) vector expressing a miR30‐based triple short‐hairpin RNA (shRNA), controlled by a muscle‐specific promoter. In a mouse hindlimb‐ischemia model, AAV9 SAV1 shRNA administration in ischemic muscles induced nuclear localization of the Hippo effector YAP, accelerated perfusion restoration, and increased exercise endurance. Intravascular lectin labeling of the vasculature revealed enhanced angiogenesis. Using 5‐ethynyl‐2′...
Source: Stem Cells - Category: Stem Cells Authors: Tags: Regenerative Medicine Source Type: research