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Defining human mesenchymal and epithelial heterogeneity in response to oral inflammatory disease.

ABSTRACT: Human oral soft tissues provide the first barrier of defence against chronic inflammatory disease and hold a remarkable scarless wounding phenotype. Tissue homeostasis requires coordinated actions of epithelial, mesenchymal, and immune cells. However, the extent of heterogeneity within the human oral mucosa and how tissue cell types are affected during the course of disease progression is unknown. Using single-cell transcriptome profiling we reveal a striking remodelling of the epithelial and mesenchymal niches with a decrease in functional populations that are linked to the aetiology of the disease. Analysis of ligand-receptor interaction pairs identify potential intercellular hubs driving the inflammatory component of the disease. Our work establishes a reference map of the human oral mucosa in health and disease, and a framework for the development of new therapeutic strategies.

SUBMITTER: Caetano AJ

PROVIDER: S-EPMC7781605 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Defining human mesenchymal and epithelial heterogeneity in response to oral inflammatory disease.

Caetano Ana J AJ Yianni Val V Volponi Ana A Booth Veronica V D'Agostino Eleanor M EM Sharpe Paul P

eLife 20210104

Human oral soft tissues provide the first barrier of defence against chronic inflammatory disease and hold a remarkable scarless wounding phenotype. Tissue homeostasis requires coordinated actions of epithelial, mesenchymal, and immune cells. However, the extent of heterogeneity within the human oral mucosa and how tissue cell types are affected during the course of disease progression is unknown. Using single-cell transcriptome profiling we reveal a striking remodelling of the epithelial and me ...[more]

PMID: 33393902

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Project description:The main functions of the choroid plexus (CP) are the production of cerebral spinal fluid (CSF), the formation of the blood-CSF barrier, and regulation of immune response. This barrier allows for the exchange of specific nutrients, waste, and peripheral immune cells between the blood stream and CSF. Borrelia burgdorferi (Bb), the causative bacteria of Lyme disease, is associated with neurological complications including meningitis-indeed, Bb has been isolated from the CSF of patients. While it is accepted that B. burgdorferi can enter the central nervous system (CNS) of patients, it is unknown how the bacteria crosses this barrier and how the pathogenesis of the disease leads to the observed symptoms in patients. We hypothesize that during infection Borrelia burgdorferi will induce an immune response conducive to the chemotaxis of immune cells and subsequently lead to a pro-inflammatory state with the CNS parenchyma. Primary human choroid plexus epithelial cells were grown in culture and infected with B. burgdorferi strain B31 MI-16 for 48 hours. RNA was isolated and used for RNA sequencing and RT-qPCR validation. Secreted proteins in the supernatant were analyzed via ELISA. Transcriptome analysis based on RNA sequencing determined a total of 160 upregulated genes and 98 downregulated genes. Pathway and biological process analysis determined a significant upregulation in immune and inflammatory genes specifically in chemokine and interferon related pathways. Further analysis revealed downregulation in genes related to cell to cell junctions including tight and adherens junctions. These results were validated via RT-qPCR. Protein analysis of secreted factors showed an increase in inflammatory chemokines, corresponding to our transcriptome analysis. These data further demonstrate the role of the CP in the modulation of the immune response in a disease state and give insight into the mechanisms by which Borrelia burgdorferi may disseminate into, and act upon, the CNS. Future experiments aim to detail the impact of B. burgdorferi on the blood-CSF-barrier (BCSFB) integrity and inflammatory response within animal models.

Project description:Background The ocular inflammatory microenvironment has been reported to be closely associated with the occurrence and progression of highly myopic cataract (HMC). Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) could alter the biological properties of mammalian cells by modulating the expression of inflammatory mediators; therefore, it may contribute to the development of HMC. Objective To investigate the function of MALAT1 in the inflammatory response, proliferation, migration, and epithelial-mesenchymal transition (EMT) of inflammatory and injured human lens epithelial cells (HLECs) and to reveal the underlying molecular signals. Methods Patients with HMC and age-related cataract (ARC) with an axial length of more than 26 mm were selected, and the anterior capsular tissue was obtained during cataract surgery. TNF-α (20 ng/mL) was chosen to induce inflammatory damage in HLECs to simulate the inflammatory microenvironment in HMC eyes. Specific siRNAs, inhibitors, and mimics were used to suppress or enhance the functions of MALAT1 and miR-26a-5p. RT-qPCR and Western blot analysis were performed to measure gene and protein expression, respectively. Results The expression of MALAT1 and the inflammatory mediators IL-6, MMP-2, and MMP-9 were significantly higher in HMC anterior capsule tissues than in ARC. TNF-α treatment increased the expression of MALAT1, while it also promoted the proliferation, migration, and EMT of HLECs. MALAT1 interference decreased the expression of IL-6 and MMP-2 and inhibited the aforementioned processes. Furthermore, MALAT1 negatively regulated the expression of miR-26a-5p and then promoted TET1 expression. TET1 was identified as a direct target of miR-26a-5p, and the promoting effect of MALAT1 on TET1 expression could be reversed by miR-26a-5p mimics. Conclusion The inflammatory environment and MALAT1 expression could be reciprocally induced in HLECs. MALAT1 may act as a ceRNA via the “sponge” miR-26a-5p and target TET1 to regulate the inflammatory response, proliferation, migration, and EMT processes in HLECs.

Dataset Information

Defining human mesenchymal and epithelial heterogeneity in response to oral inflammatory disease.

Publications

Defining human mesenchymal and epithelial heterogeneity in response to oral inflammatory disease.

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