In non-mammalian vertebrates such as birds, lost hair cells are replaced by residual supporting cells that transdifferentiate into new sensory receptors either directly or after undergoing division 6. The auditory and vestibular sensory epithelia of all vertebrates possess only two major cell types: supporting cells, which play homeostatic and architectural roles, and mechanosensitive hair cells. One prominent example of a mammalian organ with poor regenerative capacity is the inner ear 4, 5. In other instances, such as central nervous and cardiac-muscle tissues, cells exhibit little or no potential for regeneration after injury 1– 3. Regeneration occurs either by activation and amplification of resident stem cells, as in the epithelia of the skin and intestine, or through cellular de-differentiation and proliferation, as in the liver. Some adult mammalian tissues retain a gradually declining regenerative capability. Initiated in response to injury, regeneration is a complex process that can restore the structure and function of damaged tissue. Our results suggest that the pharmacological inhibition of Lats kinases may promote initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear. RNA sequencing indicates that the inhibitor reversibly activates the expression of transcriptional Yap targets: upon withdrawal, a subset of supporting-cell progeny exits the cell cycle and upregulates genes characteristic of sensory hair cells. The substance prevents Yap phosphorylation and induces proliferation of supporting cells in the murine inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. In vitro kinase assays show that the compound acts as an ATP-competitive inhibitor of Lats kinases-the core enzymes in Hippo signaling. Using a high-throughput phenotypic screen, we identified a potent and non-toxic activator of Yap. Hippo signaling is an evolutionarily conserved pathway that restricts growth and regeneration predominantly by suppressing the activity of the transcriptional coactivator Yap.
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