Laminin 332-Dependent YAP Dysregulation Depletes Epidermal Stem Cells in Junctional Epidermolysis Bullosa

摘要

Laminin 332-deficient junctional epidermolysis bullosa(JEB) is a severe genetic skin disease. JEB ismarked by epidermal stem cell depletion, the originof which is unknown. We show that dysregulationof the YAP and TAZ pathway underpins such stemcell depletion. Laminin 332-mediated YAP activitysustains human epidermal stem cells, detected asholoclones. Ablation of YAP selectively depletesholoclones, while enforced YAP blocks conversionof stem cells into progenitors and indefinitely extendsthe keratinocyte lifespan. YAP is dramaticallydecreased in JEB keratinocytes, which contain onlyphosphorylated, inactive YAP. In normal keratinocytes,laminin 332 and a6b4 ablation abolish YAPactivity and recapitulate the JEB phenotype. In JEBkeratinocytes, laminin 332-gene therapy rescuesYAP activity and epidermal stem cells in vitro andin vivo. In JEB cells, enforced YAP recapitulates laminin332-gene therapy, thus uncoupling adhesionfrom proliferation in epidermal stem cells. This workhas important clinical implication for ex vivo genetherapy of JEB.