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2 recordsLinked to original sources
PubMed2026

Homology-directed CRISPR-Cas9 correction of the KRT5 p.E475G mutation in human iPSC line from a patient with severe epidermolysis bullosa simplex.

Severe epidermolysis bullosa simplex is a skin fragility disorder characterized by blistering caused by cytolysis within basal keratinocytes, resulting in compromised epidermal integrity. Here we report the generation of the human induced pluripotent stem cell (hiPSC) line MLi002-A-1, an isogenic control derived from patient-specific MLi002-A line carrying the KRT5 c.1424A > G (p.E475G) mutation. Genome editing restored the wild-type sequence without detectable changes at top-predicted off-target sites. The edited line exhibits a normal karyotype, typical pluripotent morphology, robust pluripotency marker expression, and trilineage differentiation potential. This genetically matched control enables mutation-specific studies and in vitro modeling of epidermolysis bullosa simplex.

CRISPR-Cas9↗
PubMed2026

An isogenic hiPSC-derived keratinocyte model reveals CXCL10/CXCL11 inflammatory dysregulation in epidermolysis bullosa simplex.

Epidermolysis bullosa simplex (EBS) is a genetic skin disorder driven by dominant pathogenic variants in KRT5 or KRT14 genes, leading to cytoskeletal fragility in basal keratinocytes and intraepidermal blistering. No curative therapies are currently available, and the link between keratin mutations and disease mechanisms remains incompletely understood. To further investigate the inflammatory component of EBS, we used a model of hiPSC-derived keratinocytes carrying dominant KRT5 variants, alongside a genetically corrected isogenic counterpart. This approach established a direct link between the KRT5 variants and keratin aggregation, impaired proliferation, and an inflammatory phenotype. The inflammatory signature was confirmed by increased expression of IL1A and IL1B, consistent with previous observations in EBS, while CXCL10 and CXCL11 emerged as newly identified dysregulated chemokines. Their consistent increase across independent cell lines, elevated secretion, and normalization in the CRISPR-corrected isogenic cells indicate that KRT5 variants trigger a keratinocyte-intrinsic CXCL10/CXCL11 inflammatory response. Pharmacological inhibition of the IFN-γ-JAK1/2-STAT1 pathway suppressed their secretion, supporting JAK inhibition as a potential therapeutic strategy to modulate EBS-associated inflammatory dysregulation. In conclusion, this study shows that beyond structural defects, KRT5 variants establish a keratinocyte-intrinsic inflammatory phenotype in which the CXCL10 and CXCL11 axis emerges as a key disease-associated signature and a promising therapeutic target.

CXCL10/CXCL11↗