Human iPS-derived-keratinocytes, a new useful model to identify and explore pathological phenotype of Epidermolysis Bullosa Simplex.
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ABSTRACT:
PROVIDER: PRJNA803432 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17883454.fastq.gz | Fastqsanger.gz | |||
| SRR17883455.fastq.gz | Fastqsanger.gz | |||
| SRR17883456.fastq.gz | Fastqsanger.gz | |||
| SRR17883457.fastq.gz | Fastqsanger.gz | |||
| SRR17883458.fastq.gz | Fastqsanger.gz |
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Project description: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.
2022-04-04 | GSE196116 | GEO
Project description:The goal of this study is to characterize the expression profile of Epidermolysis bullosa simplex-mottled pigmentation (EBS-MP) patient compared with normal subjects using genomic expression analyses. Microarray analyses were performed with RNA isolated from skin biopsies. Robust multiarray analysis (RMA) normalization and Smyth’s moderated t test were used to select differentially expressed genes. Expression profiling comparisons show that 52 genes are differentially expressed in EBS-MP patients compared to control subjects. Difference of expression for three genes (TYR, CCL22 , and ACVR1C ) was validated using real-time reverse transcription–polymerase chain reaction. Twelve genes were related to lipid biosynthesis process, two to keratinisation and skin pigmentation, Nineteen to cell growth and apoptosis, five to immune response and fourteen to predicted or less known function cluster. To our knowledge, the distinctive pattern of gene expression that characterizes EBS-MP versus healthy skin tissue has never been reported. RNA used for the microarrays analysis was isolated from superficial 2mm punch biopsies composed of mainly epidermis with minimal dermis amounts of normal-appearing skin of one EBS-MP patient and seven healthy volunteers.
2012-03-10 | E-GEOD-36406 | biostudies-arrayexpress
Project description:The goal of this study is to characterize the expression profile of Epidermolysis bullosa simplex-mottled pigmentation (EBS-MP) patient compared with normal subjects using genomic expression analyses. Microarray analyses were performed with RNA isolated from skin biopsies. Robust multiarray analysis (RMA) normalization and Smyth’s moderated t test were used to select differentially expressed genes. Expression profiling comparisons show that 52 genes are differentially expressed in EBS-MP patients compared to control subjects. Difference of expression for three genes (TYR, CCL22 , and ACVR1C ) was validated using real-time reverse transcription–polymerase chain reaction. Twelve genes were related to lipid biosynthesis process, two to keratinisation and skin pigmentation, Nineteen to cell growth and apoptosis, five to immune response and fourteen to predicted or less known function cluster. To our knowledge, the distinctive pattern of gene expression that characterizes EBS-MP versus healthy skin tissue has never been reported.
2012-03-10 | GSE36406 | GEO
Project description:Epidermolysis Bullosa Simplex (EBS) is the most common form of Epidermolysis Bullosa (EB) and it is mainly inherited in an autosomal dominant manner (prevalence 1/30000 – 1/50000). Several clinical variants have been described based on the mutated gene, the site of blister formation and the anatomical distribution, but the vast majority of the patients display dominant mutations in genes encoding keratin 5 (KRT5) and keratin 14 (KRT14). The lack of functional keratin intermediate filaments causes basal keratinocytes to exhibit a dramatic cytoplasmatic softening and rupture, when subjected to minor mechanical traction, leading to the distinctive EBS patients intraepidermal blisters formation. Whilst viral mediated addition of a corrected copy of the altered gene is the ascertained approach to tackle recessively inherited EB (such as Junctional and Dystrophic EB), a potential successful combined cell and gene therapy for EBS dominant forms requires the editing of the mutated gene. In this case study, we outlined an allele specific CRISPR/Cas9 gene editing approach able to specifically detect and disrupt a de novo monoallelic c.475/495del21 mutation within exon 1 of KRT14. Taking advantage of the tailored CRISPR/Cas9 system to induce a NHEJ mediated frameshift mutations introduction, we attained a remarkable mutant allele knock-out efficiency. Following KRT14 mutant allele specific gene editing, patient derived primary keratinocytes (EBS01) restored a normal intermediate filament network and mechanical stress resilience.
2023-12-06 | GSE246343 | GEO
Project description:Epidermolysis Bullosa Simplex (EBS) is the most common form of Epidermolysis Bullosa (EB) and it is mainly inherited in an autosomal dominant manner (prevalence 1/30000 – 1/50000). Several clinical variants have been described based on the mutated gene, the site of blister formation and the anatomical distribution, but the vast majority of the patients display dominant mutations in genes encoding keratin 5 (KRT5) and keratin 14 (KRT14). The lack of functional keratin intermediate filaments causes basal keratinocytes to exhibit a dramatic cytoplasmatic softening and rupture, when subjected to minor mechanical traction, leading to the distinctive EBS patients intraepidermal blisters formation. Whilst viral mediated addition of a corrected copy of the altered gene is the ascertained approach to tackle recessively inherited EB (such as Junctional and Dystrophic EB), a potential successful combined cell and gene therapy for EBS dominant forms requires the editing of the mutated gene. In this case study, we outlined an allele specific CRISPR/Cas9 gene editing approach able to specifically detect and disrupt a de novo monoallelic c.475/495del21 mutation within exon 1 of KRT14. Taking advantage of the tailored CRISPR/Cas9 system to induce a NHEJ mediated frameshift mutations introduction, we attained a remarkable mutant allele knock-out efficiency. Following KRT14 mutant allele specific gene editing, patient derived primary keratinocytes (EBS01) restored a normal intermediate filament network and mechanical stress resilience.
2023-12-06 | GSE221645 | GEO
Project description:Gene editing in induced pluripotent stem (iPS) cells has been hailed for enabling new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa(DEB). However, manufacturing, efficacy, and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies. We developed Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a new generation GMP-compatible (cGMP), reproducible, and scalable platform to produce autologous clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts to treat incurable wounds of patients lacking type VII collagen (C7).
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Project description:Epidermolysis bullosa simplex (EBS) is a skin disorder caused by mutations in keratin (K) 5 or K14 genes. Little effect therapy is available.Following clinical reports, we applied the small molecule doxycycline to K5-/- mice. We demonstrate that doxycycline extended the survival of neonatal K5-/- mice from less than 1 to up to 8 hours. Microarray and TaqMan real-time PCR showed a downregulation of MMP-13 and IL-1ï¢, indicating an effect of doxycycline on transcription. Our data offer a novel small molecule based therapy approach for EBS. Experiment Overall Design: doxycycline (50 µg/mlwith 5 % sucrose) was administered by oral route to pregnant K5+/- females (mated to K5+/- males) starting from E13.5. 5 % sucrose solution was administered to the control group.
2008-06-15 | E-GEOD-7662 | biostudies-arrayexpress
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