GSE196116
Human iPS-derived-keratinocytes, a new useful model to identify and explore pathological phenotype of Epidermolysis Bullosa Simplex.
Epidermolysis Bullosa Simplex (EBS), an autosomal dominant skin disorder, is characterized by trauma-induced skin fragility. Genetically, majority of cases are related to missense mutations in two keratin genes, KRT5 or KRT14, leading to cytolysis of basal keratinocytes and intraepidermal blistering. Only symptomatic treatment exists for EBS patients so far. Progress towards identification of new treatments have been hampered by incomplete understanding of the mechanisms underlying this disease, and availability of relevant and reliable in vitro models recapitulating the physiopathological mechanisms. Recent advances in stem cell field have fueled the prospect that these limitations could be overcome thanks to the availability of disease-specific human induced pluripotent stem cells (hiPSC). Here we generated hiPSC-derived keratinocytes from EBS patients carrying KRT5 dominant mutations and compared them to non-affected hiPSC-derived keratinocytes as well as their primary counterparts. Our results demonstrated that EBS hiPSC-derived keratinocytes displayed proliferative defects, increased capacity to migrate, alteration of ERK signaling pathway and cytoplasmic keratin filament aggregates in response to osmotic-shock treatment in a pattern similar to primary EBS keratinocytes. Of interest, EBS hiPSC-derived keratinocytes exhibited a downregulation of hemidesmosomal proteins revealing the different effects of KRT5 mutations on keratin cytoskeletal organization. Combination of culture miniaturization and treatment with the chaperone molecule 4-Phenybutiric acid (4-PBA), our results demonstrated that hiPSC-derived keratinocytes represent a suitable model for identifying novel therapies for EBS. Overall design: Comparison of gene expression profiles of 3 hiPSC-derived WT keratinocytes and 3 hiPSC-derived EBS keratinoctyes (3 different KRT5 dominant mutations)