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Single-cell RNA-seq of isolated non-parenchymal cells from imiquimod-induced psoriasis mouse model.

ABSTRACT: We applied 10x Genomics single-cell RNA sequencing to profile non-parenchymal liver cells (NPCs) in a psoriasis-like mouse model. The study focuses on immune and liver sinusoidal endothelial cell (LSEC) alterations along the skin–liver axis to elucidate mechanisms driving comorbid liver disease in psoriasis. Given that 30–50% of psoriasis patients develop liver involvement, this approach aims to identify maladaptive cellular crosstalk and potential therapeutic targets.

ORGANISM(S): Mus musculus

PROVIDER: GSE301650 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Liver sinusoidal endothelium (LSEC) is a prime example for organ-specific microvascular differentiation and functions. Disease-associated capillarization of LSEC in vivo and dedifferentiation of LSEC in vitro indicate the importance of the hepatic microenvironment. To identify the LSEC-specific molecular differentiation program in the rat, we used a two-sided gene expression profiling approach comparing LSEC freshly isolated ex vivo with both lung microvascular endothelial cells (LMEC) and with LSEC cultured for 42h. The LSEC signature consisted of 48 genes both down-regulated in LMEC and in LSEC upon culture (FC>7 in at least one comparison); qRT-PCR confirmation of these genes included numerous family members and signalling pathway-associated molecules. The LSEC differentiation program comprised distinct sets of growth (wnt2, Fzd4, 5, 9, wls, VEGFR1, 2, 3, Nrp2) and transcription factors (Gata4, Lmo3, Tcfec, Maf) as well as endocytosis-related (Stabilin-1/2, Lyve1 and Ehd3) and cytoskeleton-associated molecules (Rnd3/RhoE). Specific gene induction in cultured LSEC versus freshly isolated LSEC as well as LMEC (Esm-1, Aatf) and up-regulation of gene expression to LMEC levels (CXCR4, Apelin) confirmed true transdifferentiation of LSEC in vitro. In addition, our analysis identified a novel 26 kDa single-pass transmembrane protein, liver endothelial differentiation-associated protein (Leda)-1, that was selectively expressed in all liver endothelial cells and preferentially localized to the abluminal cell surface. Upon forced over-expression in MDCK cells, Leda-1 was sorted baso-laterally to E-cadherin-positive adherens junctions suggesting functional involvement in cell adhesion and polarity. Conclusion: Comparative microvascular analysis in rat identified a hepatic microenvironment-dependent LSEC-specific differentiation program including the novel junctional molecule Leda-1. Highly pure liver sinusoidal endothelial cells (LSEC) and lung microvascular endothelial cells (LMEC) were isolated by enzymatic digestion, density gradient centrifugation and MACS sorting and subjected to RNA extraction and affymetrix hybridization without any culturing step (LSEC_0h, LMEC_0h). LSEC were also plated on collagen coated dishes and RNA extraction and Affymetrix hybridization was carried out after 2h and 42h in culture (LSEC_2h, LSEC_42h).

Project description:The polyphenol resveratrol has anti-inflammatory effects in various cells, tissues, animals and human settings of low-grade inflammation. Psoriasis is a disease of both localized and systemic low-grade inflammation. The Sirtuin1 enzyme thought to mediate the effects of resveratrol is present in skin and resveratrol is known to downregulate NF-κB; a major contributor in the development of psoriasis. Consequently we investigated whether resveratrol has an effect on an Imiquimod induced psoriasis-like skin inflammation in mice and sought to identify candidate genes, pathways and interleukins mediating the observed effects. The study consisted of three treatment groups: A control group, an Imiquimod group and an Imiquimod+resveratrol group. Psoriasis severity was assessed using elements of the Psoriasis Area Severity Index, actual skin thickness measurements, and histological examination. We performed an RNA microarray from lesional skin and afterwards Ingenuity pathway analysis to identify affected signalling pathways. Our microarray was compared to a previously deposited microarray to determine if gene changes were psoriasis-like, and to a human microarray to determine if findings could be relevant in a human setting. Imiquimod treatment induced a psoriasis-like skin inflammation. Resveratrol significantly diminished the severity of the psoriasis-like skin inflammation. The RNA microarray revealed a psoriasis-like gene expression-profile in the Imiquimod treated group, and highlighted several resveratrol dependent changes in relevant genes, such as increased expression of genes associated with retinoic acid stimulation and reduced expression of genes involved in IL-17 dependent pathways (e.g.IL-17A, IL-17F,IL-23p19 ). Quantitative PCR confirmed a resveratrol dependent decrease in mRNA levels of IL-17A and IL-19; both central in developing psoriasis. In conclusion, resveratrol ameliorates psoriasis, and changes in expression of retinoic acid stimulated genes, IL-17 signalling pathways, IL-17A and IL-19 mRNA levels in a beneficial manner suggests it might have a role in the treatment of psoriasis and should be explored further in a human setting.

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Single-cell RNA-seq of isolated non-parenchymal cells from imiquimod-induced psoriasis mouse model.

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