Pathological Modeling of Epidermolysis Bullosa Simplex (EBS) Using Induced Pluripotent Stem Cells (Ipsc)

Epidermolysis Bullosa simplex (EBS) is a rare disease, characterized by blistering and erosion of the skin and mucous membrane where the separation occurs within the basal layer of the epidermis due to fragility of basal keratinocytes. This disease is mostly inherited in autosomal dominant fashion, mostly due to mutations affecting either keratin 5 (KRT5) or keratin 14 (KRT14) genes. Most of reported EBS human models come from patient immortalized cell lines which limit the study of pathological phenotypes. Thanks to their capacity of self-renewal and pluripotency, human induced pluripotent stem cells (iPSC) represent an unlimited source of cells, which can be differentiated in all cell types of the organism, including skin cells. In order to better understand the cellular and molecular mechanisms associated with EBS and identify therapeutic targets, keratinocytes model using human iPSC carrying the causal mutation of EBS was developed. Keratinocytes derived from K5 EBS-iPSC (K-EBS) present at cellular level, a default of proliferation, a sensibility to osmotic shock, an enhanced formation of aggregates and an enhanced migratory activity after a scratch-wound assay. At molecular level, K-EBS present a default in the proliferative signaling pathway implicating the activation and phosphorylation of the protein ERK, as well as a default of protein quantity of hemidesmosomal proteins such as the complex integrin α6/β4, and the cytolinker Plectin. Those keratinocytes highlight phenotypes at cellular and molecular level, associated with the pathology. In light of those results, this model proves robust for the identification and understanding of the molecular mechanisms related to EBS, allowing its use for a pharmacological screening to identify molecules allowing the correction of these mechanisms.