Lacripep promotes corneal regeneration in autoimmune mediated dry eye disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA859149 | ENA |
REPOSITORIES: ENA
Similar Datasets
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: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:Dry eye syndrome (DES) is a complex ocular condition characterized by an unstable tear film and inadequate tear production, leading to tissue damage. Despite its common occurrence, there is currently no comprehensive in vitro model that accurately reproduce the cellular characteristics of DES. Here we modified a corneal epithelium-on-a-chip (CEpOC) model to recapitulate DES by subjecting HCE-T human corneal epithelial cells to an air-liquid (AL) interface stimulus. We then assessed the effects of AL stimulation both in the presence and absence of diclofenac (DCF). Transcriptomic analysis revealed distinct gene expression changes in response to AL and AL_DCF, affecting pathways related to development, epithelial structure, inflammation, and extracellular matrix remodeling. Both treatments upregulated PIEZO2, linked to corneal damage signaling, while downregulating OCLN, involved in cell-cell junctions. They increased the expression of inflammatory genes (e.g., IL6) and reduced mucin production genes (e.g., MUC16), reflecting dry eye characteristics. TGFB1, crucial for corneal wound healing, was slightly downregulated in AL_DCF, potentially affecting wound healing processes rather than reducing inflammation by DCF. Metabolomic analysis showed increased secretion of metabolites associated with cell damage and inflammation (e.g., methyl-2-oxovaleric acid, 3-methyl-2-oxobutanoic acid, lauroyl-carnitine) in response to AL and even more with AL_DCF, indicating a shift in cellular metabolism. This study showcases the utilization of AL stimulus within the CEpOC as a comprehensive approach to faithfully reproduce the cellular characteristics of DES.
2023-10-11 | GSE244787 | 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:In this study, we transferred gut microbiota of SS-like autoimmune dry eye disease model mice to conventional B6 mice (NOD-FMT). After the transfer, NOD-FMT mice experienced a dramatic change in the gut microbiomes and showed clinicopathological features of SS, including increased corneal fluorescein staining score, decreased tear production, elevated levels of IL-6 mRNA, decreased levels of MUC5AC mRNA encoding mucin. Additionally, we observed that NOD-FMT mice shared stereotypic B cell receptor (BCR) clonotypes with a much higher frequency compared to control group. B cell clones encoding these stereotypic BCR clonotypes developed and expanded locally in the lacrimal gland, and achieved systemic presence in certain clonotypes.
2024-06-26 | GSE263577 | GEO
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: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:Patients with dry eye disease (DED) often exhibit neurological abnormalities and may even suffer from neuropathic pain and pain-related anxiety or depression. However, addressing nerve abnormalities in DED remains a formidable challenge, as current therapies fail to halt disease progression. Our study found that activating α-7 nicotinic acetylcholine receptor (α7nAChR), a pivotal regulator in the anti-inflammatory pathway connecting the nervous and immune systems, effectively restores corneal epithelium integrity and enhances nerve sensitivity in DED, pointing to its promising therapeutic potential. Furthermore, we have revealed that α7nAChR stimulates genes involved in immune-mediated inflammatory progression and neuroregulation, inhibits the expression of transient receptor potential vanilloid-1 (TRPV1), reinstates corneal nerve density, and alleviates anxiety-like behaviors associated with severe DED by downregulating the proportion of CD86+ M1 macrophages (pro-inflammatory phenotypes). In summary, our findings underscore the activation of α7nAChR as a pioneering therapeutic approach for preserving corneal nerves balance and controlling inflammation in DED.
2024-04-07 | GSE263136 | GEO
Project description:We identified that Sparc gene expression is upregulated in corneal epithelial cells in a mouse model of dry eye disease involving lacrimal gland excision. Therefore, in this experiment we assess the effect of SPARC treatment on the transcriptome of human corneal epithelial cells.
2022-12-19 | GSE215149 | 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