层粘连蛋白 332 依赖性 YAP 失调导致交界性大疱性表皮松解症的表皮干细胞耗竭。
Laminin 332-Dependent YAP Dysregulation Depletes Epidermal Stem Cells in Junctional Epidermolysis Bullosa.
机构信息
Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
出版信息
Cell Rep. 2019 May 14;27(7):2036-2049.e6. doi: 10.1016/j.celrep.2019.04.055.
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 α6β4 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.
层粘连蛋白 332 缺陷性交界型大疱性表皮松解症（JEB）是一种严重的遗传性皮肤疾病。JEB 的特征是表皮干细胞耗竭，其起源尚不清楚。我们发现，YAP 和 TAZ 通路的失调是导致这种干细胞耗竭的原因。层粘连蛋白 332 介导的 YAP 活性维持着人类表皮干细胞，这些干细胞被检测为全克隆。YAP 的缺失选择性地耗尽全克隆，而强制表达 YAP 则阻止干细胞向祖细胞的转化，并无限延长角质形成细胞的寿命。JEB 角质形成细胞中的 YAP 显著减少，其中只含有磷酸化的、无活性的 YAP。在正常角质形成细胞中，层粘连蛋白 332 和α6β4 的缺失会使 YAP 失活，并重现 JEB 表型。在 JEB 角质形成细胞中，层粘连蛋白 332 的基因治疗可在体外和体内恢复 YAP 活性和表皮干细胞。在 JEB 细胞中，强制表达 YAP 可重现层粘连蛋白 332 的基因治疗效果，从而使表皮干细胞中的黏附与增殖脱耦联。这项工作对 JEB 的体外基因治疗具有重要的临床意义。
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