Transcriptome and ultrastructural changes in dystrophic Epidermolysis bullosa resemble skin aging

Breitenbach, Jenny; Rinnerthaler, Mark; Trost, Andrea; Weber, Manuela; Klausegger, Alfred; Gruber, Christina; Bruckner, Daniela; Reitsamer, Herbert A.; Bauer, Johann W.; Breitenbach, Michael

doi:10.18632/aging.100755

Cited by 35 publications

(32 citation statements)

References 104 publications

(126 reference statements)

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“…This corroborates our previous findings in plasma-treated THP-1 cells [ 83 ] and links to ROS-mediated increase in keratinocyte cell size and differentiation [ 84 ]. In support of this notion, LCE1A, which is expressed in late stages of keratinocyte maturation [ 85 ], was significantly upregulated. Filaggrin (FLG), another important component of protective skin layers of the epidermis was downregulated.…”

Section: Discussionmentioning

confidence: 77%

Periodic Exposure of Keratinocytes to Cold Physical Plasma: AnIn VitroModel for Redox-Related Diseases of the Skin

Schmidt

Woedtke

Bekeschus

2016

Oxidative Medicine and Cellular Longevity

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Oxidative stress illustrates an imbalance between radical formation and removal. Frequent redox stress is critically involved in many human pathologies including cancer, psoriasis, and chronic wounds. However, reactive species pursue a dual role being involved in signaling on the one hand and oxidative damage on the other. Using a HaCaT keratinocyte cell culture model, we investigated redox regulation and inflammation to periodic, low-dose oxidative stress after two, six, eight, ten, and twelve weeks. Chronic redox stress was generated by recurrent incubation with cold physical plasma-treated cell culture medium. Using transcriptome microarray technology, we identified both acute ROS-stress responses as well as numerous adaptions after several weeks of redox challenge. We determined a differential expression (2-fold, FDR < 0.01, p < 0.05) of 260 genes that function in inflammation and redox homeostasis, such as cytokines (e.g., IL-6, IL-8, and IL-10), growth factors (e.g., CSF2, FGF, and IGF-2), and antioxidant enzymes (e.g., HMOX, NQO1, GPX, and PRDX). Apoptotic signaling was affected rather modestly, especially in p53 downstream targets (e.g., BCL2, BBC3, and GADD45). Strikingly, the cell-protective heat shock protein HSP27 was strongly upregulated (p < 0.001). These results suggested cellular adaptions to frequent redox stress and may help to better understand the inflammatory responses in redox-related diseases.

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Section: Discussionmentioning

confidence: 77%

Periodic Exposure of Keratinocytes to Cold Physical Plasma: AnIn VitroModel for Redox-Related Diseases of the Skin

Schmidt

Woedtke

Bekeschus

2016

Oxidative Medicine and Cellular Longevity

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“…In summary, overexpression of miR-10b impacts cellular processes at various levels. The extent of the response is dependent on the cellular context, the presence of certain target mRNAs, and/or mutations in those target mRNAs [50]. In the context of cSCCs, we showed that miR-10b confers anchorage-independent spheroid formation capacities, indicating a phenotypic shift towards stem cell-like properties.…”

Section: Discussionmentioning

confidence: 88%

A cancer stem cell-like phenotype is associated with miR-10b expression in aggressive squamous cell carcinomas

et al. 2020

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Background: Cutaneous squamous cell carcinomas (cSCC) are the primary cause of premature deaths in patients suffering from the rare skin-fragility disorder recessive dystrophic epidermolysis bullosa (RDEB), which is in marked contrast to the rarely metastasizing nature of these carcinomas in the general population. This remarkable difference is attributed to the frequent development of chronic wounds caused by impaired skin integrity. However, the specific molecular and cellular changes to malignancy, and whether there are common players in different types of aggressive cSCCs, remain relatively undefined. Methods: MiRNA expression profiling was performed across various cell types isolated from skin and cSCCs. Microarray results were confirmed by qPCR and by an optimized in situ hybridization protocol. Functional impact of overexpression or knockout of a dysregulated miRNA was assessed in migration and 3D-spheroid assays. Samplematched transcriptome data was generated to support the identification of disease relevant miRNA targets. Results: Several miRNAs were identified as dysregulated in cSCCs compared to control skin. These included the metastasis-linked miR-10b, which was significantly upregulated in primary cell cultures and in archival biopsies. At the functional level, overexpression of miR-10b conferred the stem cell-characteristic of 3D-spheroid formation capacity to keratinocytes. Analysis of miR-10b downstream effects identified a novel putative target of miR-10b, the actin-and tubulin cytoskeleton-associated protein DIAPH2. Conclusion: The discovery that miR-10b mediates an aspect of cancer stemnessthat of enhanced tumor cell adhesion, known to facilitate metastatic colonizationprovides an important avenue for future development of novel therapies targeting this metastasis-linked miRNA.

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“…Those molecules are typically induced by skin damage to promote wound repair but their overexpression is related to chronic inflammation, fibrosis and cancer in RDEB (9,(67)(68)(69). MCP-1/CCL2 has also been involved in modulating the severity of the disease (70,71). Thus, targeting the TGF-β pathway might be a promising approach to symptom relief in RDEB and anti-fibrosis (3,72), and is currently being explored in a phase I/II trial (REFLECT; EudraCT:2015-003670-32).…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effect of Systemic Allogeneic Adipose Derived Mesenchymal Cells on the Clinical, Inflammatory and Immunologic Status of a Patient With Recessive Dystrophic Epidermolysis Bullosa: A Case Report

Maseda

Martínez-Santamaría²,

Sacedón

et al. 2020

Front. Med.

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Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable inherited mucocutaneous fragility disorder characterized by recurrent blisters, erosions, and wounds. Continuous blistering triggers overlapping cycles of never-ending healing and scarring commonly evolving to chronic systemic inflammation and fibrosis. The systemic treatment with allogeneic mesenchymal cells (MSC) from bone marrow has previously shown benefits in RDEB. MSC from adipose tissue (ADMSC) are easier to isolate. This is the first report on the use of systemic allogeneic ADMSC, correlating the clinical, inflammatory, and immunologic outcomes in RDEB indicating long-lasting benefits. We present the case of an RDEB patient harboring heterozygous biallelic COL7A1 gene mutations and with a diminished expression of C7. The patient presented with long-lasting refractory and painful oral ulcers distressing her quality of life. Histamine receptor antagonists, opioid analgesics, proton-pump inhibitors, and low-dose tricyclic antidepressants barely improved gastric symptoms, pain, and pruritus. Concomitantly, allogeneic ADMSC were provided as three separate intravenous injections of 106 cells/kg every 21 days. ADMSC treatment was well-tolerated. Improvements in wound healing, itch, pain and quality of life were observed, maximally at 6–9 months post-treatment, with the relief of symptoms still noticeable for up to 2 years. Remarkably, significant modifications in PBL participating in both the innate and adaptive responses, alongside regulation of levels of profibrotic factors, MCP-1/CCL2 and TGF-β, correlated with the health improvement. This treatment might represent an alternative for non-responding patients to conventional management. It seems critical to elucidate the paracrine modulation of the immune system by MSC for their rational use in regenerative/immunoregulatory therapies.

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Transcriptome and ultrastructural changes in dystrophic Epidermolysis bullosa resemble skin aging

Cited by 35 publications

References 104 publications

Periodic Exposure of Keratinocytes to Cold Physical Plasma: AnIn VitroModel for Redox-Related Diseases of the Skin

Periodic Exposure of Keratinocytes to Cold Physical Plasma: AnIn VitroModel for Redox-Related Diseases of the Skin

A cancer stem cell-like phenotype is associated with miR-10b expression in aggressive squamous cell carcinomas

Beneficial Effect of Systemic Allogeneic Adipose Derived Mesenchymal Cells on the Clinical, Inflammatory and Immunologic Status of a Patient With Recessive Dystrophic Epidermolysis Bullosa: A Case Report

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