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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE79596 | GEO | 2016/03/26

SECONDARY ACCESSION(S): PRJNA316429

REPOSITORIES: GEO

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Project description:Stem cell differentiation strategies and optimization for generating lineage-specific cells and tissues most frequently rely on a three-dimensional embryoid body (EB) intermediate. We previously applied nanotechnology tools of photolithography to generate custom microarrays that allow high throughput uniform formation of EBs of custom size for precise downstream analysis. Formation of EBs of 200 or 500 micron size revealed distinct morphological differences that are single or multicystic cores, respectively, independent of method of formation from single cells or two-dimensional (2D) clusters. Here we utilize photolithographic array generated EBs to obtain 3D cultures under a standardized platform for transcriptome analysis to compare EB size and the method of EB formation from single cells or mechanically passaged 2D clusters. Our analysis evaluates RNA expression in EBs formed from the human embryonic stem cell (hESC) line WA09 and from ethnically diverse human induced pluripotent stem cell lines (ED-iPSC) of African American and Hispanic Latino ethnicity recently derived in our laboratory. This is the first comprehensive study on EB transcriptomes including multiple size parameters, EB formation methodologies, and ethnicities. Our analysis indicates upregulation of genes involved in wound healing for mechanically passaged cells and of genes for embryonic tube formation in 500 micron multicystic EBs. We propose that EB maturation may be a longer process then previously realized. In addition, the type or extent of maturation possible may be influenced by EB size, with larger EBs capable of more extensive remodeling as revealed by multicystic morphology and initiation of early tube formation pathways while retaining pluripotency status. We anticipate that this information will be broadly useful to the stem cell and bioengineering communities in optimization of tissue engineering with pluripotent stem cells and understanding sources of variation.

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

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