MiR204-containing exosome ameliorates GVHD-associated dry eye disease
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PROVIDER: PRJNA701305 | ENA |
REPOSITORIES: ENA
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Project description:The graft-versus-host disease (GVHD) associated dry eye disease usually leads to refractory pain and visual impairment with limited treatments currently. Here we found exosome derived from mesenchymal stromal cell (MSC-exo) administered as eye drops significantly alleviates GVHD-associated dry eye disease in human and mouse models. To find out the essential elements during exosome treatment, we performed miRNA sequencing of exosomes derived from MSCs and L929 cells, and identified miR-204 in MSC-exo benefited the recovery of dry eye, which targeted IL-6/IL-6R/Stat3 signaling. Blockade of miR-204 abolished the therapeutic effect of MSC-exo while miR-204 overexpression from L929-exo markedly attenuates dry eye. Thus MSC-exo eye drops are efficacious in treating GVHD-associated dry eye and highlight miR-204 as a potential therapeutic agent.
2022-01-19 | GSE166585 | GEO
Project description:We performed single cell transcriptional profiling of mouse corneal epithelium in a mouse model of dry eye disease.
2022-12-19 | GSE182582 | GEO
Project description:Corneal architecture is essential for vision and is greatly perturbed by the absence of tears due to the highly prevalent disorder dry eye. With no regenerative therapies available, pathological alterations of the ocular surface in response to dryness, including persistent epithelial defects and poor wound healing, result in lifelong morbidity. Here, using a mouse model of aqueous-deficient dry eye, we reveal that topical application of the synthetic tear protein lacripep reverses the pathological outcomes of dry eye through restoring the extensive network of corneal nerves that are essential for tear secretion, barrier function, epithelial homeostasis and wound healing. Intriguingly, the restorative effects of lacripep occur despite extensive immune cell infiltration, suggesting tissue reinnervation and regeneration can be achieved under chronic inflammatory conditions. In summary, our data highlight lacripep as a first-in-class regenerative therapy for returning the cornea to a near homeostatic state in individuals who suffer from dry eye.
2022-07-18 | GSE208297 | GEO
Project description:Purpose: To investigate the mechanism for developing dry eye disease in the Pinkie mouse strain with a loss of function RXR mutation. Methods: Measures of dry eye disease were assessed in the cornea and conjunctiva. Expression profiling by single-cell RNA sequencing (scRNA-seq)was performed to compare gene expression in conjunctival immune cells. Conjunctival immune cells were immunophenotyped by flow cytometry and confocal microscopy. Activity of RXR ligand 9-cis retinoic acid (RA) was evaluated in cultured monocytes and T cells. Results: Compared to wild type (WT) C57BL/6, Pinkie has increased signs of dry eye disease, including corneal barrier disruption, conjunctival cornification and goblet cell loss, and corneal vascularization, opacification, and ulceration with aging. scRNA-seq of conjunctival immune cells identified T cells as the predominant IL-17 expressing population in both strains and there is a 4-fold increased percentage of T cells in Pinkie. Compared to WT, significantly increased expression of IL-17a and IL-17f in conventional T cells and IL-17f in T cells was found in Pinkie. Flow cytometry and immunostaining revealed an increased number of IL-17+ T cells in Pinkie. Tear concentration of the IL-17 inducer IL-23 is significantly higher in Pinkie. 9-cis RA treatment suppresses stimulated IL-17 production by T and stimulatory activity of monocyte supernatant on T cell IL-17 production. Compared to WT bone marrow chimeras, Pinkie chimeras have increased IL-17+ T cells in the conjunctiva after desiccating stress and anti-IL-17 treatment suppresses dry eye induced corneal MMP-9 production/activity and conjunctival goblet cell loss. Conclusion: These findings indicate that RXR suppresses generation of dry eye disease inducing T17 cells in the conjunctiva and identifies RXR as a potential therapeutic target in dry eye.
2022-01-04 | GSE192960 | GEO
Project description:Tears are a biological fluid that has diagnostic potential for ocular diseases. Extracellular vesicles (EVs), wildly detected in various biofluids including tears, are nanoparticles released by living cells and considered as promising detection sources for non-invasive liquid biopsy. Understanding the roles of tears and tear-EVs in ocular diseases such as dry eye can facilitate the studies of clinical diagnosis, which usually entails detecting such liquid objects with a rapid and effective method. In this study, we utilized a mass spectrometry based strategy to analyze peptidome/proteome profiles of tear and EVs for rapid dry eye diagnosis. Nano-sized EVs were isolated from tears of either healthy control (HC) individuals or dry eye syndrome (DES) patients, and the tear compositions were further analyzed by tracking their fingerprints with matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI-TOF-MS). The fingerprints of tear-EVs could be observed in a dose-dependent manner as well as tears, allowing comparing their discriminant peaks between tears and EVs. By analyzing these peaks, the fingerprints of both tear and tear-EVs were showed to have a capability of distinguishing DES patients from HC donors, and providing an efficient way for screening potential DES biomarkers. The proposed tear and EV fingerprinting approach is expected to be a potential tool in rapid diagnosis of ocular disease and in-depth researches of pathogenesis.
2020-08-20 | PXD020217 | Pride
Project description:Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin3 (NT-3) bind to tyrosine kinase (Trk) receptors, TrkA, TrkB, and TrkC, respectively. This study investigated the efficacy of novel molecule agonists of Trk receptors in an in vivo model of dry eye disease. Compared to vehicle, mice subjected to desiccating stress and treated with agonists pan and C1 showed improved corneal barrier function, while C1 also increased GC densities. NanoString analyses revealed upregulation of specific mRNA transcripts (Ptger4, Tnfaip3, Il1a and Ptger4, Tlr3, Osal1) in pan and C1 treated corneas compared to vehicle-treated corneas. Western blots showed pan and C1 decreased vehicle-induced NFkB nuclear translocation after DS for one day and increased PTGER4 and TNFAIP3 protein levels after 5 days of DS in corneal epithelium lysates. These results were confirmed by immunostaining using antibodies for TNFAIP3 and PTGER4 in wholemount corneas. We conclude that small-molecule agonists of Trk receptors improve dry eye disease by decreasing NFkB activation and increasing protein expression of anti-inflammatory molecules TNFAIP3 and PTGER4. Surprisingly, the most efficacious small molecule agonists were not TrkA selective, but TrkC and panTrk, suggesting that wider exploration of TrkB and C and pan Trk agonists are warranted in efforts to treat dry eye disease.
2022-05-08 | GSE202378 | GEO
Project description:Rabbit Dry Eye Diesease model induced with 3 weekly injections of Concanavalin A into the periorbital lacrimal glands Male Dutch-Belted rabbits. The pathophysiology of dry eye disease (DED) remains largely unknown, accounting in part for the lack of successful treatments. The transcriptome of full-thickness’s conjunctival tissue from rabbits with DED and from normal controls was determined using microarrays. DED induced large-scale changes in gene transcription involving 5,184 genes (22% of the total). Differentially expressed genes could be segregated into: functional modules and clusters; altered pathways; functionally linked genes; and groups of individual genes of known or suspected pathophysiological relevance to DED. A common feature of these subgroups is the breadth and magnitude of the changes that encompass ocular immunology and essentially all aspects of cell biology. Prominent changes concerned innate and adaptive immune responses; ocular surface inflammation; at least 25 significantly altered signaling pathways; a large number of chemokines; cell cycle; and apoptosis. Comparison of our findings to the limited extant transcriptomic data from DED patients associated with either Sjogren’s syndrome or non-Sjogren’s etiologies revealed a significant correlation between human and rabbit DED transcriptomes. Our data, establishing the large-scale transcriptomic changes of DED and their potential similarity to the human, underscore the enormous complexity of DED; establish a robust animal model of DED; will help expand our understanding of its pathophysiology; and could guide the development of successful therapeutic strategies.
2021-03-30 | GSE171043 | GEO
Project description:The transcriptome of rabbit conjunctiva in dry eye disease: Large-scale changes and similarity to the human dry eye
| PRJNA718236 | ENA
Project description:Lacritin targets its coreceptor 'syndecan-1' in lacritin-dependent production of the important dry eye mucin 'MUC16'. Real-time PCR analysis suggests that this effect is post-transcriptional. In contrast, serum stimulation of MUC16 by these cells is transcriptionally dependent. Our goal is to determine whether this regulation is global to other heavily O-glycosylated proteins, and if so, if it is dependent on transcription of a Golgi glycosyltransferases. If not, the mechanism might be microRNA dependent.
2011-09-06 | GSE31930 | GEO
Project description:Purpose: Identify the differentially expressed circular RNA (circRNA) and elucidate their potential function in AQP5 knockout (AQP5-/-) mice with primary dry eye phenotype. Methods: A slit lamp examination was performed on AQP5 knockout mice to assess corneal epithelial defect by fluorescein sodium staining. Hematoxylin-eosin staining and transmission electron microscope analysis were performed to access the structure of lacrimal gland epithelial cells. The expression profiles of circRNA and messenger RNA (mRNA) were determined by microarray analysis. The selected circRNA was verified by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to predict biological functions and potential pathways of parental genes involved in lacrimal gland epithelial cell changes. According to the bioinformatics analysis of identified circRNA, we can predict a circRNA-miRNA-mRNA network. Results: AQP5-/- mice exhibit spontaneous dry eye symptoms. AQP5 deficiency obviously changes the structure of lacrimal gland epithelial cells. Analysis showed that compared to AQP5+/+ mice, 30 circRNAs in the lacrimal glands of AQP5‑/- mice had differential expression (fold change ≥ 2.0, P < 0.05). Nine upregulated circRNAs were identified by qRT-PCR; nine upregulated validated circRNAs, 40 altered microRNAs (miRNAs), and nine upregulated mRNAs were involved in the network analysis. KEGG analysis showed these nine target genes were expressed in phagosomes. Conclusions: AQP5-/- mice have primary and stable dry eye phenotypes from birth. The study identified different expressed circRNAs in lacrimal glands between AQP5-/- and AQP5+/+ mice, predicting a circRNA-miRNA-mRNA network of phagosomes. CircRNA likely plays an important role in lacrimal gland epithelial cell pathogenesis. Therefore, it is reasonable to use circRNA as a potential therapeutic target for dry eyes.
2020-09-23 | GSE149832 | GEO