Laminin 332-Dependent YAP Dysregulation Depletes Epidermal Stem Cells in Junctional Epidermolysis Bullosa
Laminin 332-Dependent YAP Dysregulation Depletes Epidermal Stem Cells in Junctional Epidermolysis Bullosa
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DOI：
10.1016/j.celrep.2019.04.055
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发表时间：
2019-05-14
期刊：
影响因子：
8.8
通讯作者：
De Luca, Michele
中科院分区：
文献类型：
--
作者：
De Rosa, Laura;Seconetti, Alessia Secone;De Luca, Michele
层粘连蛋白 332 缺陷型交界性大疱性表皮松解症 (JEB) 是一种严重的遗传性皮肤病。 JEB 的特点是表皮干细胞耗竭，其来源尚不清楚。我们发现 YAP 和 TAZ 通路的失调是这种干细胞耗竭的基础。层粘连蛋白 332 介导的 YAP 活性维持人类表皮干细胞，检测为全克隆。 YAP 的消融选择性地耗尽全克隆，而强制 YAP 则阻止干细胞向祖细胞的转化，并无限期地延长角质形成细胞的寿命。 JEB 角质形成细胞中的 YAP 显着降低，该细胞仅含有磷酸化、无活性的 YAP。在正常角质形成细胞中，层粘连蛋白 332 和 α 6 β 4 消融消除了 YAP 活性并重现了 JEB 表型。在 JEB 角质形成细胞中，层粘连蛋白 332 基因疗法可在体外和体内挽救 YAP 活性和表皮干细胞。在 JEB 细胞中，强制 YAP 重现了层粘连蛋白 332 基因治疗，从而解除表皮干细胞增殖中的粘附。该工作对于JEB的离体基因治疗具有重要的临床意义。
Laminin 332-deficient junctional epidermolysis bullosa (JEB) is a severe genetic skin disease. JEB is marked by epidermal stem cell depletion, the origin of which is unknown. We show that dysregulation of the YAP and TAZ pathway underpins such stem cell depletion. Laminin 332-mediated YAP activity sustains human epidermal stem cells, detected as holoclones. Ablation of YAP selectively depletes holoclones, while enforced YAP blocks conversion of stem cells into progenitors and indefinitely extends the keratinocyte lifespan. YAP is dramatically decreased in JEB keratinocytes, which contain only phosphorylated, inactive YAP. In normal keratinocytes, laminin 332 and alpha 6 beta 4 ablation abolish YAP activity and recapitulate the JEB phenotype. In JEB keratinocytes, laminin 332-gene therapy rescues YAP activity and epidermal stem cells in vitro and in vivo. In JEB cells, enforced YAP recapitulates laminin 332-gene therapy, thus uncoupling adhesion from proliferation in epidermal stem cells. This work has important clinical implication for ex vivo gene therapy of JEB.