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Single keratinocyte analysis uncovers Foxm1 as a Yap-dependent regulator of human epidermal stem cells (scRNA-Seq)

ABSTRACT: Autologous epidermal cultures can permanently restore a functional epidermis on severely burned patients. Transgenic epidermal grafts do so also in genetic skin diseases as Junctional Epidermolysis Bullosa. Clinical success strictly requires an adequate number of epidermal stem cells, detected as holoclone-forming cells. To date, such cells can be only partially distinguished from the other transient amplifying clonogenic keratinocytes and cannot be prospectively isolated. Here we show that genome-wide single-cell transcriptome analysis performed on primary human epidermal keratinocyte cultures identified categories of genes clearly distinguishing the different clonal types, unveiled that holoclone-forming cells are enriched in genes regulating cell cycle, DNA repair (including telomerase), chromosome segregation and spindle organization, confirmed that human epidermal keratinocytes are hierarchically organized along a continuous, mainly linear trajectory showing that stem cells sequentially generate progenitors producing terminally differentiated cells and uncovered the role of FOXM1 as a YAP-dependent key regulator of normal and adhesion-defective epidermal stem cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155816 | GEO | 2021/03/18

REPOSITORIES: GEO

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Single keratinocyte analysis uncovers Foxm1 as a Yap-dependent regulator of human epidermal stem cells (microarray)

Project description:Autologous epidermal cultures can permanently restore a functional epidermis on severely burned patients. Transgenic epidermal grafts do so also in genetic skin diseases as Junctional Epidermolysis Bullosa. Clinical success strictly requires an adequate number of epidermal stem cells, detected as holoclone-forming cells. To date, such cells can be only partially distinguished from the other transient amplifying clonogenic keratinocytes and cannot be prospectively isolated. Here we show that genome-wide single-cell transcriptome analysis performed on primary human epidermal keratinocyte cultures identified categories of genes clearly distinguishing the different clonal types, unveiled that holoclone-forming cells are enriched in genes regulating cell cycle, DNA repair (including telomerase), chromosome segregation and spindle organization, confirmed that human epidermal keratinocytes are hierarchically organized along a continuous, mainly linear trajectory showing that stem cells sequentially generate progenitors producing terminally differentiated cells and uncovered the role of FOXM1 as a YAP-dependent key regulator of normal and adhesion-defective epidermal stem cells.

2021-03-18 | GSE155815 | GEO

Dowling-Meara experiment 2

Project description:Dowling-Meara type epidermolysis bullosa simplex (EBS-DM) is a severe blistering disease, caused by dominant mutations in either the keratin-5 (K5) or keratin-14 (K14) gene. K5 and K14 are the major components of the intermediate filament (IF) network in basal keratinocytes. Due to the dominant nature of EBS-DM, misfolded K5 or K14 proteins are incorporated into intermediate filaments, rendering them sensitive to mechanical stress. Upon trauma, these filaments disrupt and the keratinocytes lyse, leading to intra-epidermal blistering.The dominant nature of K5 and K14 mutations in EBS-DM represents a challenge to gene-therapeutic approaches. Therefore, we investigated the gene expression profile of a K14 mutant keratinocyte cell line (EBDM1) and compared it to the gene expression profile of a wild-type keratinocyte cell line (NEB1). The aim of this study was to identify differentially regulated genes as potential therapeutic targets for the development of new therapies.

2013-07-23 | E-MTAB-1641 | biostudies-arrayexpress

Transcriptome profiling of cultured primary recessive dystrophic epidermolysis bullosa (RDEB) squamous cell carcinoma (SCC)

Project description:Recessive dystrophic epidermolysis bullosa (RDEB) is a monogenetic skin disorder caused by mutations in the COL7A1 gene. Missing type VII collagen leads to severe blister formation and frequent chronic wounds. Patients suffering from RDEB are prone to develop particulary aggressive squamous cell carcinoma (SCC), representing the major cause of mortality. This dataset provides Affymetrix microarray (ClariomD) based whole transcriptome data on RNA isolated from cultured primary RDEB keratinocytes (RDEB-KC) as well as RDEB squamous cell carcinoma (RDEB-SCC). Cells were derived from punch biopsies or tumor resections from patients with confirmed diagnosis recessive dystrophic epidermolysis bullosa (RDEB). Primary KC and SCC were cultivated in fully defined medium till subconfluency. Total RNA was isolated and microarray assay performed.

2020-04-22 | GSE130925 | GEO

Dowling-Meara experiment 1

Project description:Dowling-Meara type epidermolysis bullosa simplex (EBS-DM) is a severe blistering disease, caused by dominant mutations in either the keratin-5 (K5) or keratin-14 (K14) gene. K5 and K14 are the major components of the intermediate filament (IF) network in basal keratinocytes. Due to the dominant nature of EBS-DM, misfolded K5 or K14 proteins are incorporated into intermediate filaments, rendering them sensitive to mechanical stress. Upon trauma, these filaments disrupt and the keratinocytes lyse, leading to intra-epidermal blistering. The dominant nature of K5 and K14 mutations in EBS-DM represents a challenge to gene therapeutic approaches. Therefore, we investigated the gene expression profile of a K14 mutant keratinocyte cell line (KEB7) and compared it to the gene expression profile of a wild-type keratinocyte cell line (NEB1). The aim of this study was to identify differentially regulated genes as potential therapeutic targets for the development of new therapies.

2013-07-23 | E-MTAB-1640 | biostudies-arrayexpress

Effects of 4-phenylbutyrate on human keratinocytes

Project description:Keratins 5 and 14 are critical for cytoskeletal integrity, as shown by missense mutations in these genes, which cause the severe skin fragility disorder epidermolysis bullosa simplex (EBS). The complexity of the pathomechanisms in EBS is not fully understood and no effective management exists. In addition to fragility, EBS keratinocytes are characterized by aggregates of misfolded keratin. Here, we tested the chemical chaperone 4-phenylbutyrate (4-PBA) as a putative novel therapy, using keratinocytes from patients with severe generalized EBS due to distinct KRT5 and KRT14 mutations.

2019-12-03 | PXD010028 | Pride

miRNA profiling of cultured primary recessive dystrophic epidermolysis bullosa (RDEB) squamous cell carcinoma (SCC)

Project description:Recessive dystrophic epidermolysis bullosa (RDEB) is a monogenetic skin disorder caused by mutations in the COL7A1 gene. Missing type VII collagen leads to severe blister formation and frequent chronic wounds. Patients suffering from RDEB are prone to develop particulary aggressive squamous cell carcinoma (SCC), representing the major cause of mortality. This dataset provides Affymetrix microarray (miRNA4.1) based whole transcriptome data on RNA isolated from cultured primary keratinocytes (KC) as well as squamous cell carcinoma (SCC). Cells were derived from punch biopsies or tumor resections from either healthy donors or SCC patients with or without the diagnosis recessive dystrophic epidermolysis bullosa (RDEB). Primary KC and SCC were cultivated in fully defined medium till subconfluency. Total RNA was isolated and microarray assay performed.

2020-04-22 | GSE130767 | GEO

Expression profiling of epidermolysis bullosa associated squamous carcinoma cells

Project description:Patients with the genetic skin blistering disease recessive dystrophic epidermolysis bullosa (RDEB) develop aggressive and metastatic cutaneous squamous cell carcinoma which is the principal cause of premature mortality in this patient group. We performed gene expression profiling of RDEB-SCC cells compared to RDEB keratinocytes in order to identify tumor-specific molecules that could potentially be exploited for detection, diagnosis, and therapy of this devastating disease.

2017-12-07 | GSE106571 | GEO

ITGA3 neg. human keratinocytes

Project description:Integrin alpha3beta1, a major epidermal adhesion receptor is critical for organization of the basement membrane during development and wound healing. Integrin alpha3 deficiency leads to interstitial lung disease, nephrotic syndrome and epidermolysis bullosa (ILNEB), an autosomal recessive multiorgan disease characterized by basement membrane abnormalities in skin, lung and kidney. The pathogenetic chains from ITGA3 mutation to tissue abnormalities are still unclear. Although integrin 3 was reported to regulate multiple extracellular proteins, the composition of the extracellular compartment of integrin alpha3-negative keratinocytes has not been resolved so far. In a comprehensive approach, quantitative proteomics of deposited extracellular matrix, conditioned cultured media as well as of the intracellular compartment of keratinocytes isolated from an ILNEB patient and from normal skin were performed. By mass spectrometry-based proteomics, 167 proteins corresponding to the GO terms “extracellular” and “cell adhesion”, or included in the “human matrisome” were identified in the deposited extracellular matrix, and 217 in the conditioned media of normal human keratinocytes. In the absence of integrin alpha3, 33% and 26% respectively were dysregulated. Dysregulated proteins were functionally related to integrin alpha3 or were known interaction partners. The results show that in the absence of integrin alpha3 ILNEB keratinocytes produce a fibronectin-rich microenvironment and make use of fibronectin-binding integrin subunits alphav and alpha5.

2018-11-27 | PXD009896 | Pride

Keratin-dependent TSLP expression suggests a link between skin blistering and atopic disease

Project description:Atopic dermatitis (AD) is a pruritic and inflammatory disorder characterized by elevated levels of thymic stromal lymphopoietin (TSLP). Pruritus is prevalent in epidermolysis bullosa (EB). Currently, epidermal barrier disruption is known to trigger TSLP upregulation, however, mechanisms controlling TSLP expression remain incompletely understood. Tslp levels were highly upregulated in the epidermis and in the serum of keratin-deficient mice. Cultured keratinocytes either lacking keratins or expressing the dominant K14p.Arg131Pro show highly increased TSLP. Re-expression of wild-type K14 normalized TSLP levels. We demonstrate that keratins regulate Tslp expression in parts through MEK1/2 activation. The finding that 8 out of 17 EBS patients show elevated TSLP serum levels supports a major role of keratins in TSLP regulation. Our data identify a novel, keratin-dependent and cell-intrinsic regulation of Tslp. Elevated TSLP levels likely explain the high prevalence of pruritus in EBS and additional forms of EB, suggesting TSLP as novel biomarker for pruritus in EB. MEK1/2, in addition to calcineurin inhibitors, might be suitable drugs to treat itch in EB. Investigation was carried out using Keratin deficient keratinocytes isolated from typeI keratin mice.

2016-03-26 | E-GEOD-79596 | biostudies-arrayexpress

RNA sequencing from epidermis of LAMA3-deficient mice

Project description:RNA sequencing data of mouse epidermis isolated from wild type and LAMA3-deficient mice Genetic, clinical and biochemical studies concurred to establish that integrity of the dermal-epidermal junction requires laminin 332, a particular subset of epithelial laminins. Laminin 332 is composed of three subunits, α3, β3 and γ2, encoded by the Lama3, Lamb3 and Lamc2 genes, respectively. In vivo functional analysis of laminin 332 in skin has been prevented because constitutive mutations of any one of the coding genes, either inherited in human or engineered in mice, cause junctional epidermolysis bullosa and early death. Consequently, it is still unknown whether and how laminin 332 contributes to skin homeostasis. To circumvent the problem, we have generated a mouse model in which disruption of the Lama3 gene is conditional and specifically induced in epidermal keratinocytes after birth. It causes a progressive depletion of laminin 332 in the skin of the mouse, which is compatible with life. To assess how laminin 332 supervises epidermal homeostasis, RNA was prepared from keratinocytes isolated from laminin 332-depleted skin and control animals (three each) to compare their gene expression profiles using RNA sequencing.

2021-02-18 | GSE146045 | GEO

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